Novel 1H-indazole compounds

ABSTRACT

The present invention provides a novel 1H-indazole compound having an excellent JNK inhibitory action. More specifically, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. 
     
       
         
         
             
             
         
       
     
     Wherein R 1  is a C 6 -C 14  aromatic cyclic hydrocarbon group etc.; R 2 , R 4  and R 5  each independently represent a hydrogen atom, a halogen atom, a cyano group etc.; L is a single bond, or a C 1 -C 6  alkylene group etc.; X is a single bond, or a group represented by —CO—NH— or —NH—CO—, etc.; and Y is a C 3 -C 8  cycloalkyl group, a C 6 -C 14  aromatic cyclic hydrocarbon group or a 5- to 14-membered aromatic heterocyclic group etc.

CROSS-REFERENCE

This application is a Divisional of co-pending application Ser. No.11/202,234 filed on Aug. 12, 2005, and for which priority is claimedunder 35 U.S.C. § 120. Priority under 35 USC § 120 is claimed throughapplication Ser. No. 11/202,234 to application Ser. No. 10/469,399,filed on Aug. 28, 2003, now U.S. Pat. No. 6,982,274 B2. Application Ser.No. 10/469,399 is the national phase of PCT International ApplicationNo. PCT/JP02/03735 filed on Apr. 15, 2002 under 35 U.S.C. § 371. Theentire contents of each of the above-identified applications are herebyincorporated by reference. This application also claims priority ofApplication No. 2001-116521 filed in Japan on Apr. 16, 2001 under 35U.S.C. § 119.

TECHNICAL FIELD

The present invention relates to a novel indazole compound having anexcellent inhibitory action on protein phosphatase (protein kinase),especially on JNK protein kinase.

PRIOR ART

A cascade by action of mitogen-activated protein kinase (hereinafterreferred to as “MAPK”) is universally presents from yeasts to humans andplays a very important role as one of intracellular signaling pathways.Among such MAPK-related kinases in mammalian cells, three types ofkinases, namely, extracellular signal-regulation kinase (ERK), p38, andc-Jun amino-terminal kinase (JNK; or also referred to asstress-activated protein kinases (SAPK)) are particularly well known.SAPKs have been found in rats and are JNK homologues, and it is knownthat isoform groups thereof each have an amino acid sequence 90% or moreequivalent to that of a corresponding isoform group of JNKs (Nature,369, 156, 1994). A multitude of activators relating to MAPK have beenidentified recently, and it has been clarified that pathways foractivating ERK, p38, and JNKs play functionally different roles,respectively. Especially, the JNK system is considered to play a role asone of medically and pharmaceutically worthy intracellular signalingpathways for the following reasons. The JNK system is possibly animportant signaling pathway that is activated by, for example, stressfactors to cells, such as tumor necrosis factor α (TNF-α), interleukin-1(IL-1), and other cytokines, as well as heat shock, ultraviolet rays(UV), and X-rays, and induces not only cell proliferation and/ordifferentiation but also apoptosis (cell death) (Science, 270, 1326,1995). JNKs were first found as a kinase for phosphatasing orylating Ser63 and Ser 73 at the N-terminus of c-Jun (Nature, 353, 670, 1991), butin recent, it has been clarified that JNKs phosphorylate manytranscription factors such as ATF-2 and Elk-1 and regulate theiractivities (EMBO J., 15, 2760, 1996). JNKs include three types, JNK 1,JNK 2 and JNK 3. JNK 1 and JNK 2 are expressed in most of tissues, butJNK 3 is particularly highly expressed in the brain (Neuron, 14, 67,1995; Neuron, 22, 667, 1999). Analyses of knocked out mice lacking JNK 1or JNK 2 have revealed that these JNKs play important roles indifferentiation and/or activation of T cells (J. Exp. Med., 193, 317,2001). In contrast, it has been reported that knocked out mice lackingJNK 3 have tolerance to spasticity initiated by kainic acid, anexcitable amino acid receptor agonist, and that the knocked out micelacking JNK 3 do not show apoptosis, which apoptosis is found inhippocampus nerve cells of normal mice after such spasticity (nature389, 865, 1997). Death of nerve cells due to apoptosis is speculated toplay an important role in nerve degeneration processes inneurodegenerative diseases such as Alzheimer's disease and Parkinson'sdisease (Experimental Neurology 133, 225, 1995; J. Neurol. Sci. 137,120, 1996), and results indicating the possibility that JNKs areinvolved in the nerve cell death have been accumulated (Neuron, 14, 67,1995; J. Neurochem., 76, 435, 2001).

For example, the following reports have been made on low-molecularsubstances having JNK inhibitory action.

(1) Compounds represented by the formula having antiinflammatory action,and compounds represented by the formula (I^(1a)) as specificembodiments thereof (WO 00/00491).

(2) 4-Aryloxyindole compounds represented by the formula (I²), andcompounds represented by the formula (I^(2a)) as specific embodimentsthereof (WO 00/35909).

(3) 4,5-Pyrazinoxyindole compounds represented by the formula (I³), andcompounds represented by the formula (I^(3a)) as specific embodimentsthereof (WO 00/35921).

(4) Compounds represented by the formula (I⁴), and compounds representedby the formula (4a) as specific embodiments thereof (WO 00/64872).

(5) Oxyindole derivatives represented by the formula (I⁵), and compoundsrepresented by the formula (I^(5a)) as specific embodiments thereof (WO00/35906).

(6) Compounds represented by the formula (I⁶) having JNK inhibitoryaction, and compounds represented by the formula (I^(6a)) as specificembodiments thereof (WO 00/75118).

(7) Compounds represented by the formula (I⁷) having JNK inhibitoryaction, and compounds represented by the formula (I^(7a)) as specificembodiments thereof (WO 01/12609).

(8) Compounds represented by the formula (I⁸) having JNK inhibitoryaction, and compounds represented by the formula (I^(8a)) as specificembodiments thereof (WO 01/12621).

(9) Sulfonamide derivatives represented by the formula (I⁹), andcompounds represented by any of the formulae (I^(9a)), (I^(9b)) and(I^(9c)) as specific embodiments thereof (WO 01/23378, WO 01/23379, andWO 01/23382).

(10) Compounds represented by the formula (II) having JNK inhibitoryaction, and compounds represented by the formula (I^(10a)) as specificembodiments thereof (EP 01/110957).

In contrast, reports have been made on compounds each having an indazoleskeleton in, for example, JP-A 2000-501105, JP-A 2000-198734 and WO99/23077. However, relations of all these compounds with protein kinasesare neither disclosed nor indicated.

As is described above, the JNK system receives attention as one ofimportant mechanisms relating to activation of various cells, regulationof immunocytes, or apoptosis of neurons induced by various stresssignals. Accordingly, compounds exhibiting inhibitory action on the JNKpathway, particularly on JNK protein kinases are expected to be usefulas therapeutic agents for various immunologic diseases, inflammatorydiseases, and/or neurodegenerative diseases. However, compounds havingexcellent JNK protein kinase inhibitory action and satisfyingrequirements in, for example, pharmacological activities, dosage, andsafety as pharmaceutical drugs have not yet been found.

DISCLOSURE OF THE INVENTION

After intensive investigations under these circumstances, the presentinventors have found novel indazole compounds having JNK inhibitoryaction. That is, the present invention relates to:

<1> a compound represented by the following formula:

(wherein R¹ is a C₆-C₁₄ aromatic cyclic hydrocarbon group which may besubstituted or a 5- to 14-membered aromatic heterocyclic group which maybe substituted;R², R⁴ and R⁵ each independently represent a hydrogen atom, a halogenatom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group,a C₁-C₆ alkyl group which may be substituted, a C₁-C₆ alkoxy group whichmay be substituted, a C₂-C₇ acyl group which may be substituted,—CO—NR^(2a)R^(2b), —NR^(2b)CO—R^(2a) or —NR^(2a)R^(2b) (wherein R^(2a)and R^(2b) each independently represent a hydrogen atom or a C₁-C₆ alkylgroup which may be substituted);L is a single bond, a C₁-C₆ alkylene group which may be substituted, aC₂-C₆ alkenylene group which may be substituted or a C₂-C₆ alkynylenegroup which may be substituted;X is a single bond, or a group represented by —NR⁶—, —O—, —CO—, —S—,—SO—, —SO₂—, —CO—NR⁸—V²—, —C(O)O—, NR⁸—CO—V²—, —NR⁸—C(O)O—, —NR⁸—S—,—NR⁸—SO—, —NR⁸—SO₂—V²—, —NR⁹—CO—NR¹⁰—, —NR⁹—CS—NR¹⁰—,—S(O)_(m)—NR¹¹—V²—, —C(═NR¹²)—NR¹³—, —OC(O)—, —OC(O)—N—R¹⁴— or—CH₂—NR⁸—COR⁶ (wherein R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ eachindependently represent a hydrogen atom, a halogen atom, a hydroxylgroup, a C₁-C₆ alkyl group which may be substituted, a C₂-C₆ alkenylgroup which may be substituted, a C₂-C₆ alkynyl group which may besubstituted, a C₁-C₆ alkoxy group which may be substituted, a C₂-C₆alkenyloxy group which may be substituted, a C₁-C₆ alkylthio group whichmay be substituted, a C₂-C₆ alkenylthio group which may be substituted,a C₃-C₈ cycloalkyl group which may be substituted, a C₃-C₈ cycloalkenylgroup which may be substituted, a 5- to 14-membered non-aromaticheterocyclic group which may be substituted, a C₆-C₁₄ aromatic cyclichydrocarbon group which may be substituted or a 5- to 14-memberedaromatic heterocyclic group which may be substituted; V² is a singlebond or a C₁-C₆ alkylene group which may be substituted; and m is 0, 1or 2); andY is a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, acyano group, a carboxyl group, a C₁-C₆ alkyl group which may besubstituted, a C₂-C₆ alkenyl group which may be substituted, a C₂-C₆alkynyl group which may be substituted, a C₁-C₆ alkoxy group which maybe substituted, a C₃-C₈ cycloalkyl group which may be substituted, aC₃-C₈ cycloalkenyl group which may be substituted, a 5- to 14-memberednon-aromatic heterocyclic group which may be substituted, a C₆-C₁₄aromatic cyclic hydrocarbon group which may be substituted, a 5- to14-membered aromatic heterocyclic group which may be substituted, anamino group or —W—R¹⁵ (wherein W is —CO— or —SO₂—; and R's is a C₁-C₆alkyl group which may be substituted, a C₆-C₁₄ aromatic cyclichydrocarbon group which may be substituted, a 5- to 14-membered aromaticheterocyclic group which may be substituted or an amino group)), a saltthereof or a hydrate of them;<2> the compound according to the above <1>, a salt thereof or a hydrateof them, wherein R², R⁴ and R⁵ each independently represent a hydrogenatom, a halogen atom or a C₁-C₆ alkoxy group which may be substituted;<3> the compound according to the above <1> or <2>, a salt thereof or ahydrate of them, wherein R⁵ is a hydrogen atom;<4> the compound according to any one of the above <1> to <3>, a saltthereof or a hydrate of them, wherein R⁴ is a hydrogen atom;<5> the compound according to any one of the above <1> to <4>, a saltthereof or a hydrate of them, wherein R² is a hydrogen atom;<6> the compound according to any one of the above <1> to <5>, a saltthereof or a hydrate of them, wherein at least one of R², R⁴ and R⁵ isnot a hydrogen atom;<7> the compound according to any one of the above <1> to <6>, a saltthereof or a hydrate of them, wherein L is a single bond or a methylenegroup;<8> the compound according to any one of the above <1> to <6>, a saltthereof or a hydrate of them, wherein L is a single bond;<9> the compound according to any one of the above <1> to <8>, a saltthereof or a hydrate of them, wherein R¹ is a C₆-C₁₄ aromatic cyclichydrocarbon group or a 5- to 14-membered aromatic heterocyclic group;and R¹ is a group which may be substituted by one to three groupsselected from the following Substituent Group “a”:<Substituent Group “a”> the group consisting of (1) (a) C₁-C₆ alkylgroups, (b) C₁-C₆ alkoxy groups, (c) C₁-C₇ acyl groups, (d) an amidogroup, (e) an amino group and (f) C₃-C₈ cycloalkyl groups, each of whichmay be substituted by one to three groups selected from the followingSubstituent Group “b”, (2) halogen atoms, (3) a hydroxyl group, (4) anitro group, (5) a cyano group, and (6) a carboxyl group;<Substituent Group “b”> the group consisting of C₁-C₆ alkyl groups,halogen atoms, a hydroxyl group, a nitro group, a cyano group and acarboxyl group;<10> the compound according to any one of the above <1> to <8>, a saltthereof or a hydrate of them, wherein R¹ is a phenyl group, a naphthylgroup or a 5- to 10-aromatic heterocyclic group; and R¹ is a group whichmay be substituted by one to three groups selected from the SubstituentGroup “a” as described in the above <9>;<11> the compound according to any one of the above <1> to <8>, a saltthereof or a hydrate of them, wherein R¹ is a phenyl group, 2-naphthylgroup, pyridyl group, 2-thienyl group, 2-furyl group, 2-benzofurylgroup, 2-quinolyl group or 2-benzothienyl group; and R¹ is a group whichmay be substituted by one to three groups selected from the SubstituentGroup “a” described in the above <9>;<12> the compound according to any one of the above <1> to <8>, a saltthereof or a hydrate of them, wherein R¹ is a 2-naphthyl group,2-benzofuryl group or 2-benzothienyl group; and R¹ is a group which maybe substituted by one to three groups selected from the SubstituentGroup “a” as described in the above <9>;<13> the compound according to any one of the above <9> to <12>, a saltthereof or a hydrate of them, wherein the Substituent Group “a” is thegroup consisting of (1) C₁-C₆ alkyl groups which may be substituted byone to three groups selected from the group consisting of a halogenatom, a hydroxyl group and a cyano group, (2) C₁-C₆ alkoxy groups whichmay be substituted by one to three groups selected from the groupconsisting of a halogen atom, a hydroxyl group and a cyano group, (3)halogen atoms, (4) a hydroxyl group, and (5) a cyano group;<14> the compound according to any one of the above <9> to <12>, a saltthereof or a hydrate of them, wherein the Substituent Group “a” ishalogen atoms;<15> the compound according to any one of the above <1> to <14>, a saltthereof or a hydrate of them, wherein X is a group represented by—CO—NR⁸—V²—, —NR⁸—CO—V²— or —NR⁸—SO₂—V²— (wherein R⁸ and V² have thesame meanings as R⁸ and V² in the above <1>);<16> the compound according to the above <15>, a salt thereof or ahydrate of them, wherein R⁸ is a hydrogen atom;<17> the compound according to any one of the above <1> to <14>, a saltthereof or a hydrate of them, wherein X is a group represented by—CO—NH—(CH₂)_(t)— (wherein t is 0 or 1);<18> the compound according to any one of the above <1> to <14>, a saltthereof or a hydrate of them, wherein X is a group represented by—NH—CO—(CH₂)_(t)— (wherein t is 0 or 1);<19> the compound according to any one of the above <1> to <18>, a saltthereof or a hydrate of them, wherein Y is a C₁-C₆ alkyl group, a C₆-C₁₄aromatic cyclic hydrocarbon group, a C₁-C₆ alkoxy group, a C₃-C₈cycloalkyl group, a 5- to 14-membered non-aromatic heterocyclic groupand a 5- to 14-membered aromatic heterocyclic group, and Y is a groupwhich may be substituted by one to three groups selected from thefollowing Substituent Group “a2”:<Substituent Group “a2”> the group consisting of (1) (a) C₁-C₆ alkylgroups, (b) C₂-C₆ alkenyl groups, (c) C₂-C₆ alkynyl groups, (d) C₁-C₆alkoxy groups, (e) C₂-C₇ acyl groups, (f) an amide group, (g) an aminogroup, (h) a C₃-C₈ cycloalkyl group, (i) C₃-C₈ cycloalkenyl groups, (j)C₆-C₁₄ aromatic cyclic hydrocarbon groups, (k) 5- to 14-memberedaromatic heterocyclic groups, (l) C₆-C₁₄ aryloxy groups, and (m) 5- to14-membered non-aromatic heterocyclic groups, each of which may besubstituted by one to three groups selected from the following<Substituent Group “b2”>, (2) halogen atoms, (3) a hydroxyl group, (4) anitro group, (5) a cyano group, and (6) a carboxyl group;<Substituent Group “b2”> the group consisting of C₁-C₆ alkyl groups,halogen atoms, a hydroxyl group, a nitro group, a cyano group, and acarboxyl group;<20> the compound according to any one of the above <1> to <18>, a saltthereof or a hydrate of them, wherein Y is a C₃-C₈ cycloalkyl group, aphenyl group, a 5- or 6-membered non-aromatic heterocyclic group or a 5-or 6-membered aromatic heterocyclic group, and Y is a group which may besubstituted by one to three groups selected from the Substituent Group“a2” as described in the above <19>;<21> the compound according to any one of the above <1> to <18>, a saltthereof or a hydrate of them, wherein Y is a furyl group, a thienylgroup, a pyrrolyl group, a phenyl group, a pyridyl group, a C₃-C₈cycloalkyl group, a tetrahydrofuran-yl group, a tetrahydrothiophenylgroup, a pyrrolidinyl group, a tetrahydrofuran-2-one-yl group, apyrrolidin-2-one-yl group or a group represented by the formula:

(wherein Y^(2a) is a group represented by —CONH₂ or —CH₂OH; and Y^(2b)and Y^(2c) each independently represent a hydrogen atom, a phenyl groupwhich may be substituted or a C₁-C₆ alkyl group which may besubstituted), and wherein Y is a group which may be substituted by oneto three groups selected from the Substituent Group “a2” as described inthe above <19>;<22> the compound according to any one of the above <1> to <18>, a saltthereof or a hydrate of them, wherein Y is a furyl group or a thienylgroup; and Y is a group which may be substituted by one to three groupsselected from the Substituent Group “a2” as described in the above <19>;<23> the compound according to any one of the above <19> to <22>, a saltthereof or a hydrate of them, wherein the Substituent Group “a2” is thegroup consisting of (1) (a) C₁-C₆ alkyl groups, (b) C₁-C₆ alkoxy groups,(c) C₁-C₇ acyl groups, (d) an amide group, (e) an amino group, and (f)C₃-C₈ cycloalkyl groups, each of which may be substituted by one tothree groups selected from the following <Substituent Group “b2”>, (2)halogen atoms, (3) a hydroxyl group, (4) a nitro group, (5) a cyanogroup, and (6) a carboxyl group, and the Substituent Group “b2” is thegroup consisting of C₁-C₆ alkyl groups, halogen atoms, a hydroxyl group,a nitro group, a cyano group, and a carboxyl group;<24> the compound according to any one of the above <19> to <22>, a saltthereof or a hydrate of them, wherein the Substituent Group “a2” is thegroup consisting of (1) C₁-C₆ alkoxy groups, (2) halogen atoms, and (3)a cyano group;<25> a c-Jun amino-terminal kinase (JNK) inhibitor, comprising thecompound according to the above <1>, a salt thereof or a hydrate ofthem.<26> c-Jun amino-terminal kinaseamino-terminal kinase 1 (JNK 1), c-Junamino-terminal kinaseamino-terminal kinase 2 (JNK 2) and/or c-Junamino-terminal kinaseamino-terminal kinase 3 (JNK 3) inhibitors,comprising the compound according to the above <1>, a salt thereof or ahydrate of them;<27> an agent for treating or preventing an immunological diseases orinflammatory diseases, comprising the compound according to the above<1>, a salt thereof or a hydrate of them;<28> the agent for treating or preventing according to the above <27>,wherein the immunological diseases or inflammatory diseases is sepsis,chronic rheumatoid arthritis, osteoarthritis, gout, psoriasis, psoriaticarthritis, bronchitis, chronic obstructive lung disease, cysticfibrosis, insulin-dependent type I diabetes, autoimmune thyroiditis,Crohn's disease, ulcerative colitis, atopic dermatitis, asthma, allergicrhinitis, hepatitis, systemic lupus erythematosus, acute and chronicgraft rejection after organ transplantation, graft versus host diseases,eczema, urticaria, myasthenia gravis, acquired immunodeficiencysyndrome, idiopathic thrombocytopenic purpura or glomerular nephritis;<29> an agent for treating or preventing neurodegenerative diseases,comprising the compound according to the above <1>, a salt thereof or ahydrate of them;<30> the agent for treating or preventing according to the above <29>,wherein the neurodegenerative diseases is acute neurodegenerativedisease;<31> the agent for treating or preventing according to the above <30>,wherein the acute neurodegenerative diseases is acute stage ofcerebrovascular disorder, head injury, spinal code injury, or neuropathydue to hypoxia or hypoglycemia;<32> the agent for treating or preventing according to the above <29>,wherein the neurodegenerative diseases is chronic neurodegenerativedisease;<33> an agent for treating or preventing Alzheimer's disease,Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis,multiple sclerosis or spinocerebellar degeneration, which comprises thecompound according to the above <1>, a salt thereof or a hydrate ofthem;<34> the agent for treating or preventing according to the above <29>,wherein the neurodegenerative disease is epilepsy, hepaticencephalopathy, peripheral neuropathy, Parkinsonian syndrome,L-DOPA-induced dyskinesia in treatment of Parkinson's disease, spasticparalysis, pain or neuralgia;<35> the agent for treating or preventing according to the above <29>,wherein the neurodegenerative disease is infectious encephalomyelitis,cerebrovascular dementia, dementia or neurosis caused by meningitis;<36> the agent for treating or preventing according to the above <35>,wherein the infectious encephalomyelitis is HIV encephalomyelitis;<37> use of the compound according to the above <1>, a salt thereof or ahydrate of them, for therapy or prophylaxis of an immunologicaldiseases, inflammatory diseases and/or neurodegenerative diseases;<38> use of the compound according to the above <1>, a salt thereof or ahydrate of them, for producing an agent for treating an immunologicaldiseases, inflammatory diseases and/or neurodegenerative diseases;<39> use of the compound according to the above <1>, a salt thereof or ahydrate of them, for producing a c-Jun amino-terminal kinase 3 (JNK 3)inhibitor;<40> a method for treating or preventing a disease against whichinhibition of c-jun amino-terminal kinaseamino-terminal kinase 3 (JNK 3)is effective, an immunological disease, an inflammatory disease and/or aneurodegenerative disease, which comprises administering apharmacologically effective amount of the compound according to theabove <1>, a salt thereof or a hydrate of them to a patient, etc.

The present invention provides a pharmaceutical composition comprisingthe compound according to claim 1, a salt thereof or a hydrate of them,and a pharmacologically acceptable carrier. The present invention alsoprovides use of the compound according to claim 1, a salt thereof or ahydrate of them, for producing an agent for treating or preventing adisease against which inhibition of a c-Jun amino-terminalkinaseamino-terminal kinase (JNK) is effective, an immunologicaldisease, an inflammatory disease or a neurodegenerative disease. Thepresent invention further provides a method for treating or preventing adisease against which inhibition of a c-Jun amino-terminal kinase (JNK)is effective, an immunological disease, an inflammatory disease or aneurodegenerative disease, which comprises administering apharmacologically effective amount of the compound according to claim 1,a salt thereof or a hydrate of them to a patient.

The meanings of symbols, terms etc. as used in the present descriptionwill be described, and the present invention will be illustrated indetail below.

The term “and/or” as used in the present description means and includesboth the cases of “and” and “or”.

The term “JNK” as used in the present description means an enzyme thatphosphorylates the N-terminus region of a c-Jun protein and includes,for example, JNK 1, JNK 2, and JNK 3. Such JNKs include three types, JNK1, JNK 2 and JNK 3. JNK 1 and JNK 2 are expressed in most of tissues,but JNK 3 is particularly highly expressed in the brain (Neuron, 14, 67,1995; Neuron, 22, 667, 1999).

The term “neurodegenerative disease(s)” as used in the presentdescription means all of diseases generally classified asneurodegenerative diseases in the field of medicine and includes, but isnot specifically limited to, “acute neurodegenerative diseases”,“chronic neurodegenerative diseases”, epilepsy, hepatic encephalopathy,peripheral neuropathy, Parkinsonian syndrome, L-DOPA-induced dyskinesiain treatment of Parkinson's disease, spastic paralysis, pain, neuralgia,infectious encephalomyelitis, cerebrovascular dementia, and dementia orneurological symptom due to meningitidis. The “acute neurodegenerativediseases” include, for example, acute stage of cerebrovascular disorder(e.g., subarachnoid hemorrhage and cerebral infarction), head injury,spinal code injury, neuropathy due to hypoxia, and neuropathy due tohypoglycemia. The “chronic neurodegenerative diseases” include, forexample, Alzheimer's disease, Parkinson's disease, Huntington's chorea,amyotrophic lateral sclerosis, multiple sclerosis, and spinocerebellardegeneration.

The term “immunologic disease(s)” or “inflammatory disease(s)” as usedin the present description means all of diseases classified asimmunologic diseases in the field of medicine, and examples thereofinclude, but are not limited to, sepsis, chronic rheumatoid arthritis,osteoarthritis, gout, psoriasis, psoriatic arthritis, bronchitis,chronic obstructive lung disease, cystic fibrosis, insulin-dependenttype I diabetes, autoimmune thyroiditis, Crohn's disease, ulcerativecolitis, atopic dermatitis, asthma, allergic rhinitis, hepatitis,systemic lupus erythematosus, acute and chronic graft rejection afterorgan transplantation, graft versus host diseases, eczema, urticaria,myasthenia gravis, acquired immunodeficiency syndrome, idiopathicthrombocytopenic purpura, and glomerular nephritis.

In the specification of the present invention, there is the case wherethe structural formula of a compound represents a definite isomer.However, the present invention includes isomers such as geometricalisomers, optical isomers based on asymmetric carbon, stereoisomers andtautomers and is not limited by the description of the formulaillustrated for the sake of convenience. Accordingly, although it ispossible that an asymmetric carbon atom is present in a molecule andaccordingly that optically active substance and racemic substance may bepresent, the present invention is not limited thereto but covers any ofthem. Further, crystal polymorphism may be present but, again, there isno limitation but any of single crystal form or a mixture will do. Thecompound (I) or its salt related to the present invention may be ananhydride or a hydrate, and either of them are included in the scope ofclaim for patent in the present invention. The metabolite which isgenerated by decomposing the compound (I) related to the presentinvention in vivo, and the prodrug of the compound (I) or its saltrelated to the present invention produce are also included in the scopeof claim for patent in the present invention.

The salts or hydrates of the compounds of the present invention arepreferably those pharmacologically acceptable.

The term “halogen atom(s)” as used in the present description includes,for example, a fluorine atom, chlorine atom, bromine atom, and iodineatom, preferably a fluorine atom and chlorine atom, and more preferablya fluorine atom.

The term “C₁-C₆ alkyl group(s)” as used in the present description meansa linear or branched alkyl group containing 1 to 6 carbon atoms andincludes, for example, methyl group, ethyl group, n-propyl group,iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group,tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group,1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group,2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group,1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutylgroup, 2-methylpentyl group, and 3-methylpentyl group. More preferredexamples are methyl group, ethyl group, n-propyl group, iso-propylgroup, n-butyl group, iso-butyl group, sec-butyl group, tert-butylgroup, and n-pentyl group.

The term “C₂-C₆ alkenyl group(s)” as used in the present descriptionmeans a linear or branched alkenyl group containing 2 to 6 carbon atomsand includes, for example, vinyl group, allyl group, 1-propenyl group,2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group,3-methyl-1-propenyl group, 2-methyl-2-propenyl group,3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenylgroup, 1-pentenyl group, 1-hexenyl group, 1,3-hexadienyl group, and1,6-hexadienyl group.

The term “C₂-C₆ alkynyl group(s)” as used in the present descriptionmeans a linear or branched alkynyl group containing 2 to 6 carbon atomsand includes, for example, ethynyl group, 1-propynyl group, 2-propynylgroup, 1-butynyl group, 2-butynyl group, 3-butynyl group,3-methyl-1-propynyl group, 1-ethynyl-2propynyl group,2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group,1,3-hexadiynyl group, and 1,6-hexadiynyl group.

The term “C₁-C₆ alkylene group(s)” as used in the present descriptionmeans a divalent group derived from the above-defined “C₁-C₆ alkylgroup” by removal of one hydrogen atom at an arbitrary position andincludes, for example, methylene group, ethylene group, methylethylenegroup, propylene group, ethylethylene group, 1,1-dimethylethylene group,1,2-dimethylethylene group, trimethylene group, 1-methyltrimethylenegroup, 1-ethyltrimethylene group, 2-methyltrimethylene group,1,1-dimethyltrimethylene group, tetramethylene group, pentamethylenegroup, and hexamethylene group, of which methylene group and1,2-ethylene group are preferred.

The term “C₂-C₆ alkenylene group(s)” as used in the present descriptionmeans a divalent group derived from the above-defined “C₂-C₆ alkenylgroup” by removal of one hydrogen atom and includes, for example,vinylene groups, propenylene groups, butenylene groups, pentenylenegroups, and hexenylene groups. Preferred examples are vinylene groups,propenylene groups, butenylene groups, and pentenylene groups, of whichvinylene groups, propenylene groups, and butenylene groups are morepreferred. Among them, 1,2-vinylene group and 1,3-propenylene group arefurther more preferred.

The term “C₂-C₆ alkynylene group(s)” as used in the present descriptionmeans a divalent group derived from the above-defined “C₂-C₆ alkynylgroup” by removal of further one hydrogen atom and includes, forexample, ethynylene group, propynylene groups, butynylene groups,pentynylene groups, and hexynylene groups. Preferred examples areethynylene group, propynylene groups, butynylene groups, and pentynylenegroups, of which ethynylene group, propynylene groups, and butynylenegroups are more preferred. Among them, ethynylene group and propynylenegroups are further more preferred, of which ethynylene group is mostpreferred.

The term “C₃-C₈ cycloalkyl group(s)” as used in the present descriptionmeans three to eight aliphatic cyclic hydrocarbon groups and includes,for example, cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, cycloheptyl group, and cyclooctyl group, of whichcyclopropyl group and cyclobutyl group are preferred.

The term “C₃-C₈ cycloalkenyl group(s)” as used in the presentdescription means a C₃-C₈ cycloalkenyl group comprising 3 to 8 carbonatoms and includes, for example, cyclopenten-3-yl, cyclohexen-1-yl, andcyclohexen-3-yl.

The term “C₁-C₆ alkoxy group(s)” as used in the present descriptionmeans an oxy group combined with the above-defined “C₁-C₆ alkyl group”and includes, for example, methoxy group, ethoxy group, n-propoxy group,iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group,sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxygroup, sec-pentyloxy group, n-hexoxy group, iso-hexoxy group,1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group,2,2-dimethylpropyloxy group, 2-ethylpropoxy group,1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group,1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxygroup, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group,2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group,3-methylpentoxy group, and hexyloxy group. Among them, methoxy group,ethoxy group, n-propoxy group, iso-propoxy group, and sec-propoxy groupare preferred, of which methoxy group and ethoxy group are morepreferred.

The term “C₂-C₆ alkenyloxy group(s)” as used in the present descriptionmeans an oxy group combined with the above-defined “C₂-C₆ alkenylgroup”.

The term “C₂-C₆ alkenylthio group(s)” as used in the present descriptionmeans a thio group combined with the above-defined “C₂-C₆ alkenylgroup”.

The term “C₁-C₆ alkoxycarbonyl group(s)” as used in the presentdescription means a carbonyl group combined with the above-defined“C₁-C₆ alkoxy group” and includes, for example, methoxycarbonyl group,ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group,n-butoxycarbonyl group, i-butoxycarbonyl group, sec-butoxycarbonylgroup, and t-butoxycarbonyl group.

The term “C₂-C₇ acyl group(s)” as used in the present description meansa carbonyl group combined with the above-defined “C₁-C₆ alkyl group” andincludes, for example, acetyl group, propionyl group, butyryl group,isobutyryl group, valeryl group, isovaleryl group, and pivaloyl group.

The term “C₁-C₆ alkylcarbamoyl group(s)” as used in the presentdescription includes, for example, methylcarbamoyl group, ethylcarbamoylgroup, n-propylcarbamoyl group, iso-propylcarbamoyl group,n-butylcarbamoyl group, iso-butylcarbamoyl group, sec-butylcarbamoylgroup, tert-butylcarbamoyl group, n-pentylcarbamoyl group,1,1-dimethylpropylcarbamoyl group, 1,2-dimethylpropylcarbamoyl group,2,2-dimethylpropylcarbamoyl group, 1-ethylpropylcarbamoyl group,2-ethylpropylcarbamoyl group, n-hexylcarbamoyl group,1-methyl-2-ethylpropylcarbamoyl group, 1-ethyl-2-methylpropylcarbamoylgroup, 1,1,2-trimethylpropylcarbamoyl group, 1-propylpropylcarbamoylgroup, 1-methylbutylcarbamoyl group, 2-methylbutylcarbamoyl group,1,1-dimethylbutylcarbamoyl group, 1,2-dimethylbutylcarbamoyl group,2,2-dimethylbutylcarbamoyl group, 1,3-dimethylbutylcarbamoyl group,2,3-dimethylbutylcarbamoyl group, 2-ethylbutylcarbamoyl group,2-methylpentylcarbamoyl group, and 3-methylpentylcarbamoyl group.

The term “C₁-C₆ alkylcarbonyloxy group(s)” as used in the presentdescription means an oxy group combined with the above-defined “C₂-C₇acyl group” and includes, for example, methylcarbonyloxy group,ethylcarbonyloxy group, n-propylcarbonyloxy group, iso-propylcarbonyloxygroup, n-butylcarbonyloxy group, iso-butylcarbonyloxy group,sec-butylcarbonyloxy group, tert-butylcarbonyloxy group,n-pentylcarbonyloxy group, 1,1-dimethylpropylcarbonyloxy group,1,2-dimethylpropylcarbonyloxy group, 2,2-dimethylpropylcarbonyloxygroup, 1-ethylpropylcarbonyloxy group, 2-ethylpropylcarbonyloxy group,n-hexylcarbonyloxy group, 1-methyl-2-ethylpropylcarbonyloxy group,1-ethyl-2-methylpropylcarbonyloxy group,1,1,2-trimethylpropylcarbonyloxy group, 1-propylpropylcarbonyloxy group,1-methylbutylcarbonyloxy group, 2-methylbutylcarbonyloxy group,1,1-dimethylbutylcarbonyloxy group, 1,2-dimethylbutylcarbonyloxy group,2,2-dimethylbutylcarbonyloxy group, 1,3-dimethylbutylcarbonyloxy group,2,3-dimethylbutylcarbonyloxy group, 2-ethylbutylcarbonyloxy group,2-methylpentylcarbonyloxy group, and 3-methylpentylcarbonyloxy group.

The term “C₁-C₆ alkylsulfonyl group(s)” as used in the presentdescription means a sulfonyl group combined with the above-defined“C₁-C₆ alkyl group” and includes, for example, methylsulfonyl group,ethylsulfonyl group, n-propylsulfonyl group, iso-propylsulfonyl group,n-butylsulfonyl group, iso-butylsulfonyl group, sec-butylsulfonyl group,tert-butylsulfonyl group, n-pentylsulfonyl group,1,1-dimethylpropylsulfonyl group, 1,2-dimethylpropylsulfonyl group,2,2-dimethylpropylsulfonyl group, 1-ethylpropylsulfonyl group,2-ethylpropylsulfonyl group, n-hexylsulfonyl group,1-methyl-2-ethylpropylsulfonyl group, 1-ethyl-2-methylpropylsulfonylgroup, 1,1,2-trimethylpropylsulfonyl group, 1-propylpropylsulfonylgroup, 1-methylbutylsulfonyl group, 2-methylbutylsulfonyl group,1,1-dimethylbutylsulfonyl group, 1,2-dimethylbutylsulfonyl group,2,2-dimethylbutylsulfonyl group, 1,3-dimethylbutylsulfonyl group,2,3-dimethylbutylsulfonyl group, 2-ethylbutylsulfonyl group,2-methylpentylsulfonyl group, and 3-methylpentylsulfonyl group.

The term “C₁-C₆ alkylsulfenyl group(s)” as used in the presentdescription means a sulfenyl group combined with the above-defined“C₁-C₆ alkyl group” and includes, for example, methylsulfenyl group,ethylsulfenyl group, n-propylsulfenyl group, iso-propylsulfenyl group,n-butylsulfenyl group, iso-butylsulfenyl group, sec-butylsulfenyl group,tert-butylsulfenyl group, n-pentylsulfenyl group,1,1-dimethylpropylsulfenyl group, 1,2-dimethylpropylsulfenyl group,2,2-dimethylpropylsulfenyl group, 1-ethylpropylsulfenyl group,2-ethylpropylsulfenyl group, n-hexylsulfenyl group,1-methyl-2-ethylpropylsulfenyl group, 1-ethyl-2-methylpropylsulfenylgroup, 1,1,2-trimethylpropylsulfenyl group, 1-propylpropylsulfenylgroup, 1-methylbutylsulfenyl group, 2-methylbutylsulfenyl group,1,1-dimethylbutylsulfenyl group, 1,2-dimethylbutylsulfenyl group,2,2-dimethylbutylsulfenyl group, 1,3-dimethylbutylsulfenyl group,2,3-dimethylbutylsulfenyl group, 2-ethylbutylsulfenyl group,2-methylpentylsulfenyl group, and 3-methylpentylsulfenyl group.

The term “C₁-C₆ alkylthio group(s)” as used in the present descriptionmeans a thio group combined with the above-defined “C₁-C₆ alkyl group”and includes, for example, methylthio group, ethylthio group,n-propylthio group, iso-propylthio group, n-butylthio group,iso-butylthio group, sec-butylthio group, tert-butylthio group,n-pentylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthiogroup, 2,2-dimethylpropylthio group, 1-ethylpropylthio group,2-ethylpropylthio group, n-hexylthio group, 1-methyl-2-ethylpropylthiogroup, 1-ethyl-2-methylpropylthio group, 1,1,2-trimethylpropylthiogroup, 1-propylpropylthio group, 1-methylbutylthio group,2-methylbutylthio group, 1,1-dimethylbutylthio group,1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group,1,3-dimethylbutylthio group, 2,3-dimethylbutylthio group,2-ethylbutylthio group, 2-methylpentylthio group, and 3-methylpentylthiogroup.

The term “C₆-C₁₄ aromatic cyclic hydrocarbon group(s)” as used in thepresent description means an aromatic cyclic hydrocarbon groupcomprising 6 to 14 carbon atoms and includes monocyclic groups as wellas bicyclic groups, tricyclic groups, and other condensed rings.Examples of these groups include phenyl group, indenyl groups,1-naphthyl group, 2-naphthyl group, azulenyl groups, heptalenyl groups,biphenyl groups, indacenyl groups, acenaphthyl groups, fluorenyl groups,phenalenyl groups, phenanthrenyl groups, anthracenyl groups,cyclopentacyclooctenyl groups, and benzocyclooctenyl groups.

In the “C₆-C₁₄ aromatic cyclic hydrocarbon group”, phenyl group,1-naphthyl group and 2-naphthyl group are preferred, and phenyl group,indenyl group and 2-naphthyl group are more preferred.

The term “C₆-C₁₄ aryloxy group(s)” as used in the present descriptionmeans an oxy group combined with the above-defined “C₆-C₁₄ aromaticcyclic hydrocarbon group”.

The term “5- to 14-membered aromatic heterocyclic group(s)” as used inthe present description means a monocyclic, bicyclic, or tricyclic 5- to14-membered heterocyclic group containing one or more hetero atomsselected from the group consisting of nitrogen atoms, sulfur atoms andoxygen atoms. Examples of the group include 1) nitrogen-containingaromatic heterocyclic groups such as pyrrolyl group, pyridyl group,pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group,tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolylgroup, benzimidazolyl group, indolyl group, isoindolyl group,indolizinyl group, purinyl group, indazolyl group, quinolyl group,isoquinolyl group, quinolidyl group, phthalazyl group, naphthyridinylgroup, quinoxalyl group, quinazolinyl group, cinnolinyl group,pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group,acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinylgroup, perimidinyl group, phenanthrolinyl group, phenazinyl group,imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinylgroup or pyrazolopyridinyl group; 2) sulfur-containing aromaticheterocyclic groups such as thienyl group or benzothienyl group; 3)oxygen-containing aromatic heterocyclic groups such as furyl group,pyranyl group, benzofuryl group or isobenzofuryl group; and 4) aromaticheterocyclic groups each containing two or more different hetero atoms,such as thiazolyl group, isothiazolyl group, benzothiazolyl group,benzthiadiazolyl group, phenothiazinyl group, isoxazoly group, furazanylgroup, phenoxazinyl group, oxazolyl group, isoxazolyl group,benzoxazolyl group, oxadiazolyl group, pyrazoloxazolyl group,imidazothiazolyl group, thienofuranyl group, furopyrrolyl group orpyridooxazinyl group.

The term “5- to 14-membered non-aromatic heterocyclic group(s)” as usedin the present description means a non-aromatic heterocyclic group 1)which comprises 5 to 14 atoms,

2) which contains one or more hetero atoms as the atoms constituting thering,3) which may contain one to three carbonyl groups, and4) which is a monocyclic, bicyclic or tricyclic ring.

Examples of the group include pyrrolidyl group, pyrrolyl group,piperidyl group, piperazyl group, imidazolyl group, pyrazolidyl group,imidazolidyl group, morpholyl group, tetrahydrofuryl group,tetrahydropyranyl group, aziridinyl group, oxiranyl group, andoxathiolanyl group. The non-aromatic heterocyclic group includes groupsderived from a pyridone ring and non-aromatic condensed rings such asgroups derived from phthalimide ring, or succinimide ring. Preferredexamples of these groups are pyrrolidyl group, pyrrolyl group, piperidylgroup, piperazyl group, imidazolyl group, pyrazolidyl group,imidazolidyl group, morpholyl group, tetrahydrofuryl group,tetrahydropyranyl group, aziridinyl group, oxiranyl group, andoxathiolanyl group.

The term “5- to 10-membered aromatic heterocyclic group(s)” as used inthe present description means a monocyclic or bicyclic aromaticheterocyclic group, whose ring comprises 5 to 10 atoms including one ormore hetero atoms.

Examples of the group include 1) nitrogen-containing aromaticheterocyclic groups such as pyrrolyl group, pyridyl group, pyridazinylgroup, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolylgroup, benzotriazolyl group, pyrazolyl group, imidazolyl group,benzimidazolyl group, indolyl group, isoindolyl group, indolizinylgroup, purinyl group, indazolyl group, quinolyl group, isoquinolylgroup, quinolidyl group, phthalazyl group, naphthyridinyl group,quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridinylgroup, imidazotriazinyl group, pyrazinopyridazinyl group,imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinylgroup or pyrazolopyridinyl group; 2) sulfur-containing aromaticheterocyclic groups such as thienyl group or benzothienyl group; 3)oxygen-containing aromatic heterocyclic groups such as furyl group,pyranyl group, benzofuryl group or isobenzofuryl group; and 4) aromaticheterocyclic groups each containing two or more different hetero atoms,such as thiazolyl group, isothiazolyl group, benzothiazolyl group,benzthiadiazolyl, isoxazoly group, furazanyl group, oxazolyl group,isoxazolyl group, benzoxazolyl group, oxadiazolyl group, pyrazoloxazolylgroup, imidazothiazolyl group, thienofuranyl group, furopyrrolyl groupor pyridooxazinyl group.

Preferred examples of the group are pyrrolyl group, furyl group, thienylgroup, pyridyl group, benzothienyl group, benzyl group, indolyl group,benzoyl group, and indazolyl group, of which furyl group, thienyl group,benzothienyl group and benzofuryl group are more preferred.

The term “5- or 6-membered aromatic heterocyclic group(s)” as used inthe present description means a monocyclic aromatic heterocyclic group,whose ring comprises 5 or 6 atoms including one or more hetero atoms.Examples of the group include pyrrolyl group, imidazolyl group,pyrazolyl group, 1,2,3-triazolyl group, pyridyl group, pyridazyl group,pyrimidinyl group, pyrazinyl group, furyl group, thienyl group,thiazolyl group, oxazolyl group, and isoxazolyl group, of which pyrrolylgroup, pyridyl group, furyl group and thienyl group are preferred. Amongthem, furyl group and thienyl group are more preferred.

The term “5- or 6-membered non-aromatic heterocyclic group(s)” as usedin the present description means a 5- or 6-membered heterocyclic groupcontaining one or more hetero atoms selected from the group consistingof nitrogen atoms, sulfur atoms and oxygen atoms. Examples of the groupinclude piperidyl group, piperazyl group, morpholyl group, thiomorpholylgroup, tetrahydro-2-pyron-yl group, tetrahydropyran-yl groups,tetrahydrothiopyran-yl groups, piperidin-2-one-yl groups,tetrahydrofuran-yl group, tetrahydrothiophen-yl group, pyrrolidinylgroup, tetrahydrofuran-2-one-yl groups, and pyrrolidin-2-one-yl groups.Preferred examples of the “5- or 6-membered nonaromatic heterocyclicgroup” are piperidyl group, piperazyl group, morpholyl group,thiomorpholyl group, tetrahydro-2-pyron-yl groups, tetrahydropyran-ylgroups, tetrahydrothiopyran-yl groups, and piperidin-2-one-yl groups.

The term “5-membered non-aromatic heterocyclic group(s)” as used in thepresent description means a 5-membered heterocyclic group containing oneor more hetero atoms selected from the group consisting of nitrogenatoms, sulfur atoms, and oxygen atoms and concretely means, for example,tetrahydrofuran-yl group, tetrahydrothiophen-yl group, pyrrolidinylgroup, tetrahydrofuran-2-one-yl groups, or pyrrolidin-2-one-yl groups.

The term “amino group(s)” as used in the present description means agroup represented by the formula —NH₂.

The term “amide group(s)” as used in the present description means agroup represented by the formula —CO—NH₂.

The term “furyl group” as used in the present description means 2-furylgroup or 3-furyl group, of which 2-furyl group is preferred.

The term “thienyl group” as used in the present description means2-thienyl group or 3-thienyl group, of which 2-thienyl group ispreferred.

The term “pyrrolyl group” as used in the present description means1-pyrrolyl group, 2-pyrrolyl group, or 3-pyrrolyl group, of which2-pyrrolyl group is preferred.

The term “tetrahydrofuran-yl group” as used in the present descriptionmeans tetrahydrofuran-2-yl group or tetrahydrofuran-3-yl group, of whichtetrahydrofuran-2-yl group is preferred.

The term “tetrahydrothiophen-yl group” as used in the presentdescription means tetrahydrothiophen-2-yl group ortetrahydrothiophen-3-yl group, of which tetrahydrothiophen-2-yl group ispreferred.

The term “pyrrolidinyl group” as used in the present description means1-pyrrolidinyl group, 2-pyrrolidinyl group, or 3-pyrrolidinyl group, ofwhich 2-pyrrolidinyl group is preferred.

The term “tetrahydrofuran-2-one-yl group” as used in the presentdescription means tetrahydrofuran-2-one-3-yl group,tetrahydrofuran-2-one-4-yl group, or tetrahydrofuran-2-one-5-yl group,of which tetrahydrofuran-2-one-5-yl group is preferred.

The term “pyrrolidin-2-one-yl group” as used in the present descriptionmeans pyrrolidin-2-one-1-yl group, pyrrolidin-2-one-3-yl group,pyrrolidin-2-one-4-yl group, or pyrrolidin-2-one-5-yl group, of whichpyrrolidin-2-one-5-yl group is preferred.

The term “quinolyl group” as used in the present description means amonovalent group derived from a quinoline ring by removal of any onehydrogen atom and includes, for example, 2-quinolyl group, 3-quinolylgroup, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolylgroup, and 8-quinolyl group, of which 2-quinolyl group is preferred.

Preferred examples of the group represented by the formula:

(wherein Y^(2a), Y^(2b) and Y^(2c) have the same meanings as definedabove) are groups represented by the following formulae:

The term “may be substituted” as used in the present description has thesame meaning as in “may have one or plural substituents in an arbitrarycombination at positions(s) that can be substituted”.

Typical examples of the substituent in the term “may be substituted” asused in the present description include:

(1) halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom, andiodine atom);(2) hydroxyl group;(3) cyano group;(4) nitro group;(5) carboxyl group;(6) amino group;(7) C₁-C₆ alkyl groups (e.g., methyl group, ethyl group, n-propyl group,iso-propyl group, n-butyl group, tert-butyl group, n-pentyl group,1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropylgroup, 1-ethylpropyl group, 2-ethylpropyl group, and n-hexyl group);(8) C₂-C₆ alkenyl groups (e.g., vinyl group, allyl group, 1-propenylgroup, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group,and 3-methyl-1-propenyl group);(9) C₂-C₆ alkynyl groups (e.g., ethynyl group, 1-propynyl group,2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group,3-methyl-1-propynyl group, 1-ethynyl-2propynyl group, and2-methyl-3-propynyl group);(10) C₃-C₈ cycloalkyl groups (e.g., cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctylgroup);(11) C₃-C₈ cycloalkenyl groups (e.g., cyclopropen-1-yl,cyclopropen-3-yl, cyclobuten-1-yl, cyclobuten-3-yl,1,3-cyclobutadien-1-yl, cyclopenten-1-yl, cyclopenten-3-yl,cyclopenten-4-yl, 1,3-cyclopentadien-1-yl, 1,3-cyclopentadien-2-yl,1,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl,cyclohexen-4-yl, 1,3-cyclohexadien-1-yl, 1,3-cyclohexadien-2-yl,1,3-cyclohexadien-5-yl, 1,4-cyclohexadien-3-yl, and1,4-cyclohexadien-1-yl);(12) C₁-C₆ alkoxy groups (e.g., methoxy group, ethoxy group, n-propoxygroup, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxygroup, sec-butoxy group, tert-butoxy group, n-pentyloxy group,iso-pentyloxy group, sec-pentyloxy group, n-hexoxy group, iso-hexoxygroup, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, and2,2-dimethylpropyloxy group);(13) C₁-C₆ alkenyloxy groups (e.g., vinyloxy group, allyloxy group,1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group,2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group,2-methyl-2-propenyloxy group, 3-methyl-2-propenyloxy group, 1-butenyloxygroup, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group,1-hexenyloxy group, 1,3-hexadienyloxy group, and 1,6-hexadienyloxygroup);(14) C₁-C₆ alkylthio groups (e.g., methylthio group, ethylthio group,n-propylthio group, iso-propylthio group, n-butylthio group,iso-butylthio group, sec-butylthio group, tert-butylthio group,n-pentylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthiogroup, 2,2-dimethylpropylthio group, 1-ethylpropylthio group,2-ethylpropylthio group, n-hexylthio group, and1-methyl-2-ethylpropylthio group);(15) C₁-C₆ alkenylthio groups (e.g., vinylthio group, allylthio group,1-propenylthio group, 2-propenylthio group, isopropenylthio group,2-methyl-1-propenylthio group, 3-methyl-1-propenylthio group,2-methyl-2-propenylthio group, 3-methyl-2-propenylthio group,1-butenylthio group, 2-butenylthio group, 3-butenylthio group,1-pentenylthio group, 1-hexenylthio group, 1,3-hexadienylthio group, and1,6-hexadienylthio group);(16) C₁-C₁₄ aryloxy groups (e.g., phenyloxy group);(17) C₂-C₇ acyl groups (e.g., acetyl group, propionyl group, andbutyloyl group);(18) C₆-C₁₄ aromatic cyclic hydrocarbon groups (e.g., phenyl group,1-naphthyl group, and 2-naphthyl group);(19) 5- to 14-membered non-aromatic cyclic hydrocarbon groups (e.g., 1)pyrrolidyl group, pyrrolyl group, piperidyl group, piperazyl group,imidazolyl group, pyrazolidyl group, imidazolidyl group, morpholylgroup, tetrahydrofuryl group, tetrahydropyranyl group, aziridinyl group,oxiranyl group, and oxathiolanyl group;2) groups derived from a pyridone ring; and3) groups derived from condensed rings such as phthalimide ring andsuccinimide ring);(20) 5- to 14-membered aromatic heterocyclic groups (e.g., pyrrolylgroup, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinylgroup, imidazolyl group, benzimidazolyl group, indolyl group, indazolylgroup, quinolyl group, isoquinolyl group, thienyl group, benzothienylgroup, furyl group, pyranyl group, benzofuryl group, thiazolyl group,and benzothiazolyl group);(21) amide group;(22) sulfonyl groups each having a C₁-C₆ aliphatic hydrocarbon group asa substituent;(23) sulfonamide group;(24) C₁-C₆ alkyl-carbamoyl groups;(25) C₁-C₆ alkoxy-carbonyl groups;(26) C₁-C₆ alkyl-carbonyloxy groups;(27) C₁-C₆ alkylsulfonyl groups;(28) C₁-C₆ alkylsulfinyl groups;(29) formyl group;(30) groups represented by the following formula:

wherein R^(11a) and R^(11a) each independently represent a hydrogen atomor a C₁-C₆ alkyl group;(31) groups represented by the following formula:

wherein R^(10a) and R^(11a) each independently represent a hydrogen atomor a C₁-C₆ alkyl group; and(32) groups represented by the following formula:

wherein R^(10a) and R^(11a) each independently represent a hydrogen atomor a C₁-C₆ alkyl group. The term “may be substituted” as used in thepresent description means that may have one to four substituentsselected from the group consisting of these substituents.

Further, in the aforementioned substituents (6) to (23) as thesubstituent in “may be substituted”, the amino group, C₁-C₆ alkylgroups, C₂-C₆ alkenyl groups, C₂-C₆ alkynyl groups, C₃-C₈ cycloalkylgroups, C₃-C₈ cycloalkenyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkenyloxygroups, C₁-C₆ alkylthio groups, C₁-C₆ alkenylthio groups, C₁-C₁₄ aryloxygroups, C₂-C₇ acyl groups, C₆-C₁₄ aromatic cyclic hydrocarbon groups, 5-to 14-membered non-aromatic cyclic hydrocarbon groups or 5- to14-membered aromatic heterocyclic groups, amide group, sulfonyl groupseach having a C₁-C₆ aliphatic hydrocarbon group as a substituent, orsulfonamide group may be further substituted by one to four groupsselected from the group consisting of:

(a) halogen atoms,(b) hydroxyl group,(c) cyano group,(d) nitro group,(e) carboxyl group,(f) amino group,(g) C₁-C₆ alkyl groups,(h) C₂-C₆ alkenyl groups,(i) C₂-C₆ alkynyl groups,(j) C₃-C₈ cycloalkyl groups,(k) C₃-C₈ cycloalkenyl groups,(l) C₁-C₆ alkoxy groups,(m) C₁-C₆ alkenyloxy groups,(n) C₁-C₆ alkylthio groups,(o) C₁-C₆ alkenylthio groups,(p) C₁-C₁₄ aryloxy groups,(q) C₂-C₇ acyl groups,(r) C₆-C₁₄ aromatic cyclic hydrocarbon groups,(s) 5- to 14-membered non-aromatic cyclic hydrocarbon groups,(t) 5- to 14-membered aromatic heterocyclic groups,(u) amido group,(v) sulfonyl groups each having a C₁-C₆ aliphatic hydrocarbon group as asubstituent, and(w) sulfonamido group described in (1) to (23).

Preferred examples of the substituent in the term “may be substituted”as used in the present description include:

(a-1) halogen atoms,(a-2) hydroxyl group,(a-3) nitrile group,(a-4) C₁-C₆ alkyl groups, C₂-C₆ alkenyl groups, C₂-C₆ alkynyl groups,C₃-C₈ cycloalkyl groups and C₁-C₆ alkoxy groups, each of which may besubstituted by one to three halogen atoms or hydroxyl groups,(a-5) C₆-C₁₀ aromatic cyclic hydrocarbon groups,(a-6) 5- to 14-membered aromatic heterocyclic groups,(a-7) 5- to 14-membered heterocyclic groups,(a-8) carboxyl group,(a-9) trifluoromethyl group,(a-10) C₁-C₆ alkylcarbamoyl groups,(a-11) C₁-C₆ alkoxycarbonyl groups,(a-12) C₂-C₇ acyl groups,(a-13) C₁-C₆ alkylcarbonyloxy groups,(a-14) C₁-C₆ alkylsulfonyl groups,(a-15) C₁-C₆ alkylsulfinyl groups,(a-16) C₁-C₆ alkylthio groups,(a-17) nitro group,(a-18) formyl group,(a-19) groups represented by the formula:

wherein R^(10a) and R^(11a) each independently represent a hydrogen atomor a C₁-C₆ alkyl group, and (a-20) groups represented by the formula:

wherein R^(10a) and R^(11a) each independently represent a hydrogen atomor a C₁-C₆ alkyl group, and(a-21) groups represented by the formula:

wherein R^(10a) and R^(11a) each independently represent a hydrogen atomor a C₁-C₆ alkyl group.

More preferred examples of the substituent in the term “may besubstituted” as used in the present description include:

(a-1) halogen atoms,(a-2) hydroxyl group,(a-3) nitrile group,(a-4) C₁-C₆ alkyl groups, C₃-C₈ cycloalkyl groups or C₁-C₆ alkoxygroups, each of which may be substituted by one to three halogen atomsor hydroxyl groups,(a-17) nitro group,(a-19) groups represented by the formula:

wherein R^(10a) and R^(11a) each independently represent a hydrogen atomor a C₁-C₆ alkyl group, and(a-20) groups represented by the formula:

wherein R^(10a) and R^(11a) each independently represent a hydrogen atomor a C₁-C₆ alkyl group.

Still more preferred examples of the substituent in the term “may besubstituted” as used in the present description include halogen atoms,nitrile group, C₁-C₆ alkyl groups, C₃-C₈ cycloalkyl groups, C₁-C₆ alkoxygroups, and trifluoromethyl group.

Further more preferred examples of the substituent in the term “may besubstituted” as used in the present description include fluorine atom,cyclopropyl group, trifluoromethyl group, and methoxy group.

General Synthesis Method

Typical production processes of the 1H-indazole compounds represented bythe formula (I) according to the present invention will be illustratedbelow. In reaction schemes of the following Production Processes 1 to40, R is a C₁-C₈ alkyl group; R¹, R², R⁴, and R⁵ have the same meaningsas defined above; R³ is a group represented by the formula -L-X—Y(wherein L, X and Y have the same meanings as the above-defined L, X andY); T¹ is a hydrogen atom, a bromine atom or an iodine atom; T² is ahalogen atom; T³ is a sulfonate or a halogen atom; T⁴ is a hetero atom(oxygen atom, nitrogen atom or sulfur atom); “Pro” represents aprotecting group; Q is a C₁-C₈ alkyl group; Q¹, Q² and Q³ eachindependently represent a C₁-C₈ alkyl group, or Q¹ and Q² may becombined to form a ring; Q⁴ and Q⁵ each independently represent a grouprepresented by the formula —Y (wherein Y has the same meaning as definedabove); R^(1a) is a group represented by the formula R¹ (wherein R¹ hasthe same meaning as defined above); R¹⁹ has the same meaning as theabove-defined group represented by R², R⁴ or R⁵; and p is an integer of0, 1, 2, or 3.

Production Process 1

The compound (I) can be produced by treating the fluorobenzene 1 with,for example, an alkyllithium or lithium amide to thereby yield a metalaryl, allowing the metal aryl to react with an acrylaldehyde to therebyyield the alcohol 2, oxidizing the alcohol 2 into the ketone 3, and thenclosing the indazole ring with hydrazine. The alkyllithium forconverting the fluorobenzene 1 to the metal aryl includes, for example,n-butyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium.Where necessary, an additive such asN,N,N′,N′-tetramethylethylenediamine and hexamethylphosphoramide can beadded. The lithium amide includes, for example, lithiumdiisopropylamide, and lithium 2,2,6,6-tetramethylpiperidide. Solventsfor use herein are not specifically limited, as long as they are inertto the reaction, and preferred examples thereof are ether solvents suchas diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as wellas benzene and toluene. A reaction temperature is from −78° C. to roomtemperature. Oxidizing agents for oxidizing the alcohol compound 2include, for example, manganese dioxide, sulfur trioxide-pyridinecomplex, N-methylmorpholine-N-oxide, and chromic acid oxidizing agents.The oxidation can also be performed by Swern oxidation or Moffatoxidation. Solvents for use herein can be any solvents that are notinvolved in the reaction and include, for example, halogenatedhydrocarbons such as dichloromethane or chloroform, as well as ethylacetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide. Areaction temperature is generally from −78° C. to the reflux temperatureof the solvent. The reaction for cyclization of the compound 3 withhydrazine monohydrate can be performed in the absence of, or in thepresence of, a solvent. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction, and include, forexample, ether solvents such as diethyl ether, tetrahydrofuran, dioxaneor dimethoxyethane, alcohol solvents such as methanol, ethanol orpropanol, as well as pyridine, dimethyl sulfoxide, benzene, and toluene.The amount of the hydrazine monohydrate is from 2 to 20 equivalents tothe raw material. A reaction temperature is generally from 0° C. to thereflux temperature of the solvent.

Production Process 2

The compound 2 can also be produced by Production Process 2. Initially,the fluorobenzene 1 is converted into to a metal aryl by the procedureof Production Process 1, and the metal aryl is allowed to react with aformylation agent to yield the compound 4. The formylation agentincludes, for example, dimethylformamide, N-formylpiperidine, andmethylphenylformamide. Reaction solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene andtoluene. A reaction temperature is from −78° C. to room temperature. Thecompound 2 can be produced by allowing the compound 4 to react with ametal aryl or metal halogenoaryl. The metal aryl or metal halogenoarylcan be easily prepared, for example, by treating a halogenoaryl using analkyllithium, magnesium or zinc into an arylithium or metalhalogenoaryl. The alkyllithium includes, for example, n-butyllithium,sec-butyllithium, tert-butyllithium, and phenyllithium. Where necessary,an additive such as N,N,N′,N′-tetramethylethylenediamine andhexamethylphosphoramide can be added. Reaction solvents for use hereinare not specifically limited, as long as they are inert to the reaction,and include, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene andtoluene. A reaction temperature is from −78° C. to room temperature.

Production Process 3

The compound (I) can also be produced by halogenating the 3-position ofthe indazole compound 5 to yield the compound 6, protecting the1-position of the compound 6 to yield the compound 7, subjecting thecompound 7 to Suzuki coupling with an arylboronic acid to yield thecompound 8, and deprotecting the 1-position of the compound 8. Reagentsfor halogenating the 3-position include, for example,N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide, and bromine.Where necessary, a radical reaction initiator such as2,2′-azobisisobutyronitrile and benzoyl peroxide can be added. Theamount of the halogenation reagent is from 1.05 to 1.2 equivalents tothe raw material. Solvents for use herein are not specifically limited,as long as they are inert to the reaction, and include, for example,halogenated hydrocarbons such as dichloromethane, chloroform or carbontetrachloride, as well as ethyl acetate, acetonitrile, dimethylsulfoxide, and dimethylformamide. A reaction temperature is generallyfrom room temperature to the reflux temperature of the solvent.

Protecting groups for the 1-position include, for example,tert-butyloxycarbonyl group, p-toluenesulfonyl group, triphenylmethylgroup, and methoxymethyl group. The tert-butyloxycarbonyl group orp-toluenesulfonyl group can be introduced by allowing the compound 6 toreact with di-tert-butyl dicarbonate or p-toluenesulfonyl chloride inthe presence of a base. Such bases are not specifically limited butpreferred examples are triethylamine and 4-N,N-dimethylaminopyridine.Solvents for use herein are not specifically limited, as long as theyare inert to the reaction and include, for example, ether solvents suchas diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane,halogenated hydrocarbons such as dichloromethane or chloroform, as wellas ethyl acetate, acetonitrile, dimethyl sulfoxide, anddimethylformamide. A reaction temperature is generally from 0° C. to thereflux temperature of the solvent.

The triphenylmethyl group or methoxymethyl group can be introduced byallowing the compound 6 to react with chlorotriphenylmethane orchloromethyl methyl ether in the presence of a base. Such bases are notspecifically limited, but preferred examples are sodium hydride,potassium tert-butoxide, lithium diisopropylamide, potassium carbonate,and sodium hydroxide. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction and include, forexample, ether solvents such as diethyl ether, tetrahydrofuran, dioxaneor dimethoxyethane, as well as ethyl acetate, acetonitrile, dimethylsulfoxide, and dimethylformamide. A reaction temperature is generallyfrom −20° C. to the reflux temperature of the solvent.

Among arylboronic acids for use in Suzuki coupling, those commerciallyavailable will be purchased, and those not commercially available can beeasily prepared according to a conventional procedure. Such anarylboronic acid can be prepared, for example, by treating ahalogenoaryl with an alkyllithium, magnesium or zinc to convert the sameinto an arylithium or a metal halogenoaryl, allowing the arylithium ormetal halogenoaryl to react with trialkyl-borate into a boric ester, andhydrolyzing the boric ester. The alkyllithium includes, for example,n-butyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium.Where necessary, an additive such asN,N,N′,N′-tetramethylethylenediamine, and hexamethylphosphoramide can beadded. The boric ester formed as a result of the reaction between thearylithium and the trialkyl-boric acid can be hydrolyzed by adding wateror by using an acid such as hydrochloric acid or sulfuric acid. Reactionsolvents for use herein are not specifically limited, as long as theyare inert to the reaction, of which ether solvents such as diethylether, tetrahydrofuran, dioxane or dimethoxyethane are preferred. Areaction temperature is from −78° C. to room temperature. The amount ofthe arylboronic acid for use in Suzuki coupling is from 1 to 3equivalents to the raw material. Catalysts for use herein include, forexample, palladium(II) acetate,dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0). The amount of the catalyst isabout 5% by mole relative to the raw material. Where necessary, aphosphine ligand in an amount of two times by mole that of the catalystcan be added. Such phosphine ligands include, for example,tri-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl,2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine. Examples ofbases for use herein are sodium hydrogencarbonate, sodium carbonate,potassium carbonate, cesium carbonate, and potassium fluoride. Solventsfor use herein are not specifically limited, as long as they do notadversely affect the reaction, and include, for example,dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, and toluene. A reaction temperature isgenerally from room temperature to the reflux temperature of thesolvent.

The tert-butyloxycarbonyl group and triphenylmethyl group can be easilydeprotected (removed) by using an acid. Such acids include, for example,hydrochloric acid, sulfuric acid, and trifluoroacetic acid. Wherenecessary, a radical scavenger such as thiophenol ortri-iso-propylsilane can be added. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, halogenated hydrocarbons such as dichloromethaneor chloroform, alcohol solvents such as methanol or ethanol, andanisole. A reaction temperature is from −20° C. to the refluxtemperature of the solvent. The tert-butyloxycarbonyl group andp-toluenesulfonyl group can also be easily deprotected by using a base.Such bases include, but are not specifically limited to, aqueous sodiumhydroxide and aqueous potassium hydroxide. Solvents for use herein arenot specifically limited, as long as they are inert to the reaction, andinclude, for example, alcohol solvents such as methanol or ethanol,ether solvents such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane. A reaction temperature is room temperature to thereflux temperature of the solvent. The methoxymethyl group can bedeprotected by treating the compound with an acid and treating theresidual aminal with aqueous ammonia.

Production Process 4

The compound 8 can also be obtained by converting the compound 7 intothe boronic acid 9 and subjecting the boronic acid 9 to Suzuki couplingwith an aryl halide or aryl sulfonate. The boronic acid 9 can beobtained by converting the compound 7 into an arylithium, allowing thearylithium to react with trialkyl-borate to yield a boric ester, andhydrolyzing the boric ester. The alkyllithium for converting thecompound 7 into an arylithium includes, for example, n-butyllithium,sec-butyllithium, tert-butyllithium, and phenyllithium. Where necessary,an additive such as N,N,N′,N′-tetramethylethylenediamine andhexamethylphosphoramide can be added. The boric ester formed as a resultof the reaction between the arylithium and the trialkyl borate can behydrolyzed by adding water or by using an acid such as hydrochloric acidor sulfuric acid. Reaction solvents for use herein are not specificallylimited, as long as they are inert to the reaction, of which ethersolvents such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane are preferred. A reaction temperature is from −78° C. toroom temperature. The compound 8 can be produced by subjecting theboronic acid 9 and an aryl halide or aryl sulfonate to Suzuki couplingunder the conditions of Production Process 3.

Production Process 5

The compound 8 can also be produced by Stille coupling as shown inProduction Process 5. Among aryltrialkyltins for use in Stille coupling,those commercially available will be purchased and those notcommercially available can be easily prepared. Such an aryltrialkyltincan be prepared, for example, by treating a halogenoaryl with analkyllithium, magnesium, or zinc to thereby yield an arylithium or metalhalogenoaryl, and allowing the arylithium or metal halogenoaryl to reactwith a chlorotrialkyltin or hexaalkylditin. Reaction solvents for useherein are not specifically limited, as long as they are inert to thereaction, of which ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane are preferred. A reactiontemperature is from −78° C. to room temperature. The amount of thearyltrialkyltin for use in Stille coupling is from 1 to 3 equivalents tothe raw material. Catalysts for use herein include, for example,palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0). The amount of the catalyst isabout 5% by mole relative to the raw material. Where necessary, aphosphine ligand in an amount of two times by mole that of the catalystcan be added. Such phosphine ligands include, for example,tri-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl,2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine. Solvents foruse herein are not specifically limited, as long as they do notadversely affect the reaction, and include, for example,dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, toluene, and xylenes. A reactiontemperature is generally from room temperature to the reflux temperatureof the solvent.

Production Process 6

The compound 8 can also be obtained by converting the compound 7 intothe tin compound 10, and subjecting the tin compound 10 to Stillecoupling with an aryl halide or aryl sulfonate. The tin compound 10 canbe obtained by converting the compound 7 into an arylithium under thesame conditions as in Production Process 4, and allowing the arylithiumto react with a chlorotrialkyltin or hexaalkylditin. Reaction solventsfor use herein are not specifically limited, as long as they are inertto the reaction, of which ether solvents diethyl ether, tetrahydrofuran,dioxane or dimethoxyethane are preferred. A reaction temperature is from−78° C. to room temperature. The compound 8 can be produced bysubjecting the tin compound 10 and an aryl halide or aryl sulfonate toStille coupling under conditions of Production Process 5.

Production Process 7

The compound (I) can also be produced by subjecting the compound 6 inwhich the 1-position is not protected to Stille coupling underconditions of Production Process 5, as shown in Production Process 7.

Production Process 8

The compound 8 can also be produced by subjecting to Stille couplingwith tributyl(1-ethoxyvinyl)tin, treating the resulting compound withN-bromosuccinimide to yield the bromoacetyl 11, and converting thebromoacetyl 11 to an aromatic ring, as shown in Production Process 8.The tributyl(1-ethoxyvinyl)tin for use in Stille coupling iscommercially available. The amount of the tributyl(1-ethoxyvinyl)tin isfrom 1 to 3 equivalents to the raw material. Catalysts for use hereinare not specifically limited, of whichtetrakis(triphenylphosphine)palladium(0) is preferred. The amount of thecatalyst is about 5% by mole relative to the raw material. Solvents foruse herein are not specifically limited, as long as they do notadversely affect the reaction, and preferred examples thereof aretetrahydrofuran, dioxane, diethylene glycol dimethyl ether, toluene, andxylenes. A reaction temperature is generally from room temperature tothe reflux temperature of the solvent. The bromination can be performedby exchanging the solvent with tetrahydrofuran or dioxane, and addingabout 1 equivalent of N-bromosuccinimide. The compound 11 can beconverted into an aromatic ring by allowing the compound to react with,for example, 2-aminopyridine or thiourea in the presence of a base. Suchbases include, but are not specifically limited to, sodiumhydrogencarbonate, sodium carbonate, potassium carbonate, and sodiumhydride. Solvents for use herein are not specifically limited, as longas they are inert to the reaction, and include, for example, alcoholsolvents methanol or ethanol, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, as well as ethyl acetate,acetonitrile, dimethyl sulfoxide, and dimethylformamide. A reactiontemperature is generally 0° C. to the reflux temperature of the solvent.

Production Process 9

As shown in Production Process 9, the compound 8 can also be produced bysubjecting the compound 7 to Sonogashira coupling withtrimethylsilylacetylene, detrimethylsililating the resulting compound toyield the compound 12, subjecting the compound 12 to coupling with thehalogenated aromatic cyclic compound 13 having a hydroxyl group, aminogroup or thiol group at the ortho-position, each of which may beprotected by a protecting group, and aromatically cyclizing theresulting compound under the same conditions after deprotecting theprotecting group, if any. The trimethylsilylacetylene for use inSonogashira coupling is commercially available. The amount of thetrimethylsilylacetylene is from 1 to 3 equivalents to the raw material.Catalysts for use herein include, but are not specifically limited to,palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0). The amount of the catalyst isabout 10% by mole relative to the raw material. Where necessary, anadditive such as copper(I) iodide or triphenylphosphine can be added inan amount 1 to 2 times that of the catalyst. Bases for use hereininclude, but are not specifically limited to, triethylamine,diisopropylamine, and piperidine. Solvents for use herein are notspecifically limited, as long as they do not adversely affect thereaction, of which dimethylformamide, tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, toluene, and xylenes are preferred. Areaction temperature is generally from room temperature to the refluxtemperature of the solvent.

The detrimethylsilanization can be easily performed by using a fluorineanion or an acid. Such fluorine anions for use herein include, forexample, tetrabutylammonium fluoride, hydrogen fluoride, potassiumfluoride, and cesium fluoride. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, halogenated hydrocarbons such as dichloromethaneor chloroform, alcohol solvents such as methanol or ethanol, water,diethyl ether, tetrahydrofuran, dioxane; and toluene. A reactiontemperature is from −20° C. to the reflux temperature of the solvent.Acids for use herein include, for example, hydrochloric acid, sulfuricacid, and trifluoroacetic acid. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, halogenated hydrocarbons such as dichloromethaneor chloroform, alcohol solvents such as methanol or ethanol, diethylether, and tetrahydrofuran. A reaction temperature is from −20° C. tothe reflux temperature of the solvent.

Among the compounds 13, those commercially available will be purchased,and those not commercially available can be produced, for example, byprotecting a hetero atom of an aromatic cyclic compound having ahydroxyl group, amino group or thiol group, treating the protectedcompound with an alkyllithium or lithium amide to yield a metal aryl,and halogenating the metal aryl.

Protecting groups for T⁴ include, for example, tert-butyloxycarbonylgroup, pivaloyl group, and methoxymethyl group. These protecting groupscan be introduced by allowing an aromatic cyclic compound having ahydroxyl group, amino group or thiol group to react with di-tert-butyldicarbonate, pivaloyl chloride or chloromethoxymethyl in the presence ofa base. Such bases for use herein include, but are not specificallylimited to, triethylamine, 4-N,N-dimethylaminopyridine, sodium hydride,potassium tert-butoxide, lithium diisopropylamide, potassium carbonate,and sodium hydroxide. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction, and include, forexample, ether solvents such as diethyl ether, tetrahydrofuran, dioxaneor dimethoxyethane, halogenated hydrocarbons such as dichloromethane orchloroform, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide,and dimethylformamide. A reaction temperature is generally from 0° C. tothe reflux temperature of the solvent.

The alkyllithium for converting the aromatic cyclic compound having theprotected T⁴ into the metal aryl includes, for example, n-butyllithium,sec-butyllithium, tert-butyllithium, and phenyllithium. Where necessary,an additive such as N,N,N′,N′-tetramethylethylenediamine orhexamethylphosphoramide can be added. The lithium amide includes, forexample, lithium diisopropylamide, and lithium2,2,6,6-tetramethylpiperidide. Preferred examples of the halogenatingagent are iodine, N-iodosuccinimide, bromine, and N-bromosuccinimide.Solvents for use herein are not specifically limited, as long as theyare inert in the reaction, and include, for example, ether solvents suchas diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as wellas benzene and toluene. A reaction temperature is from −78° C. to roomtemperature.

The amount of the compound 13 for use in the coupling reaction betweenthe compounds 12 and 13 is from 1 to 2 equivalents to the raw material12. Catalysts for use herein include, but are not specifically limitedto, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II),and tetrakis(triphenylphosphine)palladium(0). The amount of the catalystis about 10% by mole relative to the raw material. Where necessary, anadditive such as copper(I) iodide or triphenylphosphine can be added inan amount 1 to 2 times that of the catalyst. Bases for use hereininclude, but are not specifically limited to, triethylamine,diisopropylamine, and piperidine. Solvents for use herein are notspecifically limited, as long as they do not adversely affect thereaction, of which dimethylformamide, tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, toluene, and xylenes are preferred. Areaction temperature is generally from room temperature to the refluxtemperature of the solvent. When the hetero atom of the compound 13 isnot protected, the compound can undergo aromatic cyclization under theseconditions.

When the hetero atom of the compound 13 is protected, the compound isdeprotected after coupling and can undergo aromatic cyclization underthe same conditions as in coupling. The protecting group of T⁴ can beeasily deprotected by using an acid or a base. Such acids include, forexample, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.Solvents for use herein are not specifically limited, as long as theyare inert to the reaction, and include, for example, halogenatedhydrocarbons dichloromethane or chloroform, alcohol solvents such asmethanol or ethanol. A reaction temperature is from −20° C. to thereflux temperature of the solvent. The base is not specifically limitedand includes, for example, aqueous sodium hydroxide and aqueouspotassium hydroxide. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction, and include, forexample, alcohol solvents methanol or ethanol, ether solvents such asdiethyl ether, tetrahydrofuran, dioxane or dimethoxyethane. A reactiontemperature is from room temperature to the reflux temperature of thesolvent.

Production Process 10

The compound 8 can also be produced by subjecting the compound 7 tocoupling with the compound 14, deprotecting the coupling product toyield the compound 15, and aromatically cyclizing the compound 15, asshown in Production Process 10. The compound 14 can be syntheticallyprepared by subjecting the compound 13 to Sonogashira coupling withtrimethylsilylacetylene, and detrimethylsilylating the coupling product.The trimethylsilylacetylene for use in Sonogashira coupling iscommercially available. The amount of the trimethylsilylacetylene isfrom 1 to 3 equivalents to the raw material. Catalysts for use hereininclude, but are not specifically limited to, palladium(II) acetate,dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0). The amount of the catalyst isabout 10% by mole relative to the raw material. Where necessary, anadditive such as copper(I) iodide or triphenylphosphine can be added inan amount 1 to 2 times that of the catalyst. Bases for use hereininclude, but are not specifically limited to, triethylamine,diisopropylamine, and piperidine. Solvents for use herein are notspecifically limited, as long as they do not adversely affect thereaction, of which dimethylformamide, tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, toluene, and xylenes are preferred. Areaction temperature is generally from room temperature to the refluxtemperature of the solvent.

The detrimethylsilanization can be easily performed by using a fluorineanion or an acid. Such fluorine anions for use herein include, forexample, tetrabutylammonium fluoride, hydrogen fluoride, potassiumfluoride, and cesium fluoride. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, halogenated hydrocarbons dichloromethane orchloroform, alcohol solvents such as methanol or ethanol, water, diethylether, tetrahydrofuran, dioxane, and toluene. A reaction temperature isfrom −20° C. to the reflux temperature of the solvent. Acids for useherein include, for example, hydrochloric acid, sulfuric acid, andtrifluoroacetic acid. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction, and include, forexample, halogenated hydrocarbons such as dichloromethane or chloroform,alcohol solvents such as methanol or ethanol. A reaction temperature isfrom −20° C. to the reflux temperature of the solvent.

The amount of the compound 14 in the coupling reaction between thecompounds 14 and 7 is from 1 to 2 equivalents to the raw material 7.Catalysts for use herein include, but are not specifically limited to,palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0). The amount of the catalyst isabout 10% by mole relative to the raw material. Where necessary, anadditive such as copper(I) iodide or triphenylphosphine can be added inan amount 1 to 2 times that of the catalyst. Bases for use hereininclude, but are not specifically limited to, triethylamine,diisopropylamine, and piperidine. Solvents for use herein are notspecifically limited, as long as they do not adversely affect thereaction, of which dimethylformamide, tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, toluene, and xylenes are preferred. Areaction temperature is generally from room temperature to the refluxtemperature of the solvent.

The protecting group of T⁴ can be easily deprotected by using an acid ora base. Such acids include, for example, hydrochloric acid, sulfuricacid, and trifluoroacetic acid. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, halogenated hydrocarbons such as dichloromethaneor chloroform, alcohol solvents such as methanol or ethanol. A reactiontemperature is from −20° C. to the reflux temperature of the solvent.The base is not specifically limited and includes, for example, aqueoussodium hydroxide and aqueous potassium hydroxide. Solvents for useherein are not specifically limited, as long as they are inert to thereaction, and include, for example, alcohol solvents such as methanol orethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxaneor dimethoxyethane. A reaction temperature is from room temperature tothe reflux temperature of the solvent. By performing aromaticcyclization of the compound 15 under the same conditions as in thecoupling between the compound 7 and the compound 14, the compound 8 canbe produced.

Production Process 11

The compound (I) can also be produced by subjecting the aniline 16 andan aryl acid chloride to a Friedel-Crafts reaction to yield the ketone17, converting the aniline derivative into a diazonium salt, reducingthe diazonium salt with tin chloride, and closing the ring of theresulting compound. Lewis acids for use in the Friedel-Crafts reactionfor the production of the ketone 17 include, for example, aluminium(III)chloride and ethylaluminum dichloride. Solvents for use herein arepreferably halogen-containing solvents such as methylene chloride orchloroform. A reaction temperature is generally from −50° C. to thereflux temperature of the solvent. The ketone 17 can be converted intothe diazonium salt by allowing the ketone 17 to react with sodiumnitrite in the presence of an acid. Reaction solvents for use hereininclude, for example, alcohol solvents such as methanol or ethanol, aswell as hydrochloric acid, sulfuric acid, and acetic acid. A reactiontemperature is generally from 0° C. to room temperature. The diazoniumsalt can be reduced and the indazole ring can be closed by allowing thediazonium salt to react with tin(II) chloride in the presence of anacid. Reaction solvents for use herein include, for example, alcoholsolvents such as methanol or ethanol, as well as hydrochloric acid,sulfuric acid, and acetic acid. A reaction temperature is generally from0° C. to room temperature.

Practical production processes of 3-arylindazole compounds includingproduction processes for the side chain moiety thereof will beillustrated below, but they are not limited thereto.

Production Process 12

The compound (I)-a can be produced by converting theortho-halogenofluorobenzene 18 into a lithium aryl, allowing the lithiumaryl to react with an aryl aldehyde to yield the alcohol 19, oxidizingthe alcohol 19 into the ketone 20, converting the acetal into the ester,treating the ester with hydrazine into the indazole 22, hydrolyzing theindazole 22 into the carboxylic acid 23, and amidating the carboxylicacid 23.

Alkyllithiums for converting the ortho-halogenofluorobenzene 18 into thelithium aryl include, for example, n-butyllithium, sec-butyllithium,tert-butyllithium, and phenyllithium. Where necessary, an additive suchas N,N,N′,N′-tetramethylethylenediamine or hexamethylphosphoramide canbe added. Solvents for use herein are not specifically limited, as longas they are inert to the reaction, and preferred examples thereof areether solvents such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane, as well as benzene and toluene. A reaction temperatureis from −78° C. to room temperature.

Oxidizing agents for oxidizing the alcohol 19 include, for example,manganese dioxide, sulfur trioxide-pyridine complex,N-methylmorpholine-N-oxide, and chromic acid oxidizing agents. Theoxidation can also be performed by Swern oxidation or Moffat oxidation.Solvents for use herein can be any solvents that are not involved in thereaction and include, for example, halogenated hydrocarbons such asdichloromethane or chloroform, as well as ethyl acetate, acetonitrile,dimethyl sulfoxide, and dimethylformamide. A reaction temperature isgenerally from −78° C. to the reflux temperature of the solvent.

The ester 21 can be produced by treating with an acid into the aldehyde,oxidizing the aldehyde into the carboxylic acid, and esterifying thecarboxylic acid. Acids for use in conversion into the aldehyde include,but are not specifically limited to, p-toluenesulfonic acid, pyridiniump-toluenesulfonate, hydrochloric acid, and sulfuric acid. Solvents foruse herein can be any solvents that are not involved in the reaction andinclude, for example, alcohol solvents such as methanol or ethanol, aswell as acetone, and tetrahydrofuran. A reaction temperature isgenerally from room temperature to the reflux temperature of thesolvent. Oxidizing agents for oxidizing the aldehyde into the carboxylicacid include, for example, Jones reagents and sodium chlorite. Solventsfor use herein can be any solvents that are not involved in the reactionand include, for example, halogen-containing solvents such as methylenechloride or chloroform, as well as ethyl acetate, dimethylformamide, anddimethyl sulfoxide. A reaction temperature is generally from 0° C. tothe reflux temperature of the solvent. The carboxylic acid can beconverted into the ester, for example, by allowing the carboxylic acidwith an alkyl iodide in the presence of a base or to react withdiazomethane. Examples of bases for use herein include sodium hydride,potassium carbonate, and potassium tert-butoxide. A reaction temperatureis generally from 0° C. to the reflux temperature of the solvent.

The cyclization of the ester 21 with hydrazine monohydrate can beperformed in the absence of, or in the presence of, a solvent. Solventsfor use herein are not specifically limited, as long as they are inertto the reaction, and include, for example, ether solvents such asdiethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, alcoholsolvents such as methanol, ethanol or propanol, as well as pyridine,dimethyl sulfoxide, benzene, and toluene. The amount of the hydrazinemonohydrate is from 2 to 20 equivalents to the raw material. A reactiontemperature is generally from 0° C. to the reflux temperature of thesolvent.

The ester 22 can be easily hydrolyzed by using, for example, aqueoussodium hydroxide or aqueous potassium hydroxide. Solvents for use hereincan be any solvents that are not involved to the reaction and include,for example, alcohol solvents such as methanol or ethanol, as well astetrahydrofuran, dioxane, and other ether solvents. A reactiontemperature is generally from 0° C. to the reflux temperature of thesolvent.

The carboxylic acid 23 can be amidated by treating with an amine and acondensing agent. Such condensing agents include, for example,dicyclohexylcarbodiimide, diisopropylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Wherenecessary, 1-hydroxybenzotriazole and/or N-hydroxysuccinimide can beadded. Solvents for use herein can be any solvents that are not involvedin the reaction and include, for example, halogen-containing solventssuch as methylene chloride or chloroform, ether solvents such as etheror tetrahydrofuran, as well as ethyl acetate, dimethylformamide, andtoluene. A reaction temperature is generally from room temperature tothe reflux temperature of the solvent.

Production Process 13

The alcohol 19 can also be produced by converting theortho-halogenofluorobenzene 18 into a lithium aryl by the procedure ofProduction Process 12, allowing the lithium aryl to react with aformylation agent to yield the aldehyde 24, and allowing the aldehyde 24to react with a metal aryl or metal halogenoaryl. Formylation agents forformylation of the lithium aryl prepared from theortho-halogenofluorobenzene 18 by the procedure of Production Process 12include, for example, dimethylformamide, N-formylpiperidine, andmethylphenylformamide. Reaction solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene andtoluene. A reaction temperature is from −78° C. to room temperature. Themetal aryl or metal halogenoaryl for the reaction with the aldehyde 24can be easily prepared by the procedure of Production Process 2.Reaction solvents for use herein are not specifically limited, as longas they are inert to the reaction, and include, for example, ethersolvents such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane, as well as benzene and toluene. A reaction temperatureis from −78° C. to room temperature.

Production Process 14

The carboxylic acid 23 can also be produced by treating thefluorobenzene 25 with, for example, an alkyllithium or lithium amide toyield an lithium aryl, allowing the lithium aryl to react with an arylaldehyde to yield the alcohol 26, oxidizing the alcohol 26 into theketone 27, treating the ketone 27 with hydrazine to yield the indazole28, and hydrolyzing the nitrile.

The alkyllithium for converting the fluorobenzene 25 into the lithiumaryl includes, for example, n-butyllithium, sec-butyllithium,tert-butyllithium, and phenyllithium. Where necessary, an additive suchas N,N,N′,N′-tetramethylethylenediamine or hexamethylphosphoramide canbe added. The lithium amide includes, for example, lithiumdiisopropylamide, and lithium 2,2,6,6-tetramethylpiperidide. Solventsfor use herein are not specifically limited, as long as they are inertto the reaction, and preferred examples thereof are ether solvents suchas diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as wellas benzene and toluene. A reaction temperature is from −78° C. to roomtemperature. The compound 28 can be produced by oxidizing the alcoholand closing the indazole ring with the use of hydrazine monohydrate bythe procedure of Production Process 12. The nitrile moiety of thecompound 28 can be hydrolyzed by using an acid or a base. Such acidsinclude, for example, hydrochloric acid and hydrous sulfuric acid. Thereaction can be performed in the absence of, or in the presence of asolvent. Such solvents include, for example, alcohol solvents such asmethanol, ethanol or propanol, as well as acetic acid. A reactiontemperature is generally from room temperature to the reflux temperatureof the solvent. The base includes, for example, sodium hydroxide andpotassium hydroxide. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction, of which alcoholsolvents such as methanol, ethanol or propanol are preferred. A reactiontemperature is generally from room temperature to the reflux temperatureof the solvent.

Production Process 15

The compound (I)-b can be prepared by protecting the 1-position of theester 22 produced in Production Process 12 to yield the compound 29,reducing the compound 29 into the alcohol 30, converting the alcohol 30into a sulfonate or halogen 31, converting the same into the cyanocompound 32 and then into the carboxylic acid 33, and amidating thecarboxylic acid 33. Protecting groups for protecting the 1-position ofthe ester 22 include, for example, tert-butyloxycarbonyl group,p-toluenesulfonyl group, triphenylmethyl group, and methoxymethyl group.The tert-butyloxycarbonyl group and p-toluenesulfonyl group can beintroduced by allowing the ester 22 to react with di-tert-butyldicarbonate or p-toluenesulfonyl chloride in the presence of a base.Such bases are not specifically limited, and preferred examples aretriethylamine and 4-N,N-dimethylaminopyridine. Solvents for use hereinare not specifically limited, as long as they are inert to the reactionand include, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbonssuch as dichloromethane or chloroform, as well as pyridine, ethylacetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide. Areaction temperature is generally from 0° C. to the reflux temperatureof the solvent. The triphenylmethyl group and methoxymethyl group can beintroduced by allowing the ester 22 to react with chlorotriphenylmethaneor chloromethyl methyl ether in the presence of a base. Such bases arenot specifically limited, and preferred examples are sodium hydride,potassium tert-butoxide, lithium diisopropylamide, potassium carbonate,and sodium hydroxide. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction and include, forexample, ether solvents such as diethyl ether, tetrahydrofuran, dioxaneor dimethoxyethane, as well as pyridine, ethyl acetate, acetonitrile,dimethyl sulfoxide, and dimethylformamide. A reaction temperature isgenerally from −20° C. to the reflux temperature of the solvent.Reducing agents for reducing the ester moiety of the compound 29include, for example, di-iso-butylaluminium hydride, lithium aluminiumhydride, and lithium borohydride. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction andinclude, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene andtoluene. A reaction temperature is generally from −20° C. to the refluxtemperature of the solvent. The alcohol 30 can be converted into thesulfonate by allowing the alcohol 30 to react with a sulfonyl chloridein the presence of a base. Examples of the sulfonyl chloride aremethanesulfonyl chloride, and p-toluenesulfonyl chloride. Bases for useherein are not specifically limited and include, for example,triethylamine, 4-dimethylaminopyridine, and sodium hydride. Solvents foruse herein are not specifically limited, as long as they are inert tothe reaction and include, for example, ether solvents such as diethylether, tetrahydrofuran, dioxane or dimethoxyethane, halogen-containingsolvents such as methylene chloride or chloroform, as well as pyridine,benzene, toluene, and dimethylformamide. A reaction temperature is from−20° C. to the reflux temperature of the solvent. By performing thereaction in dichloromethane in the presence of triethylamine for a longtime, a chloride can be obtained. The sulfonate and chloride can beconverted into an iodide by allowing the same to react with about 1.1equivalent of sodium iodide in acetone at room temperature. The nitrile32 can be obtained by allowing the sulfonate or halide 31 to react withsodium cyanide or potassium cyanide. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction andinclude, for example, alcohol solvents such as methanol or ethanol,ether solvents such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane, as well as dimethylformamide, and dimethyl sulfoxide. Areaction temperature is from −20° C. to the reflux temperature of thesolvent. The nitrile 32 can be hydrolyzed by using an acid. Such acidsinclude, for example, hydrochloric acid and hydrous sulfuric acid. Thereaction can be performed in the absence of, or in the presence of asolvent. Such solvents include, for example, alcohol solvents such asmethanol, ethanol or propanol, as well as acetic acid. A reactiontemperature is generally from room temperature to the reflux temperatureof the solvent. In this reaction, the protecting group is removedconcurrently. By amidating the carboxylic acid 33 by the procedure ofProduction Process 12, the compound (I)-b can be produced.

Production Process 16

The compound 30 can also be produced by reducing the ester 22 having anon-protected 1-position produced in Production Process 12, andprotecting the 1-position. The ester 22 is reduced by the procedure ofProduction Process 15 to thereby yield the alcohol 34. Then, aprotecting group is introduced into the 1-position of the alcohol 34 bythe procedure of Production Process 15 to thereby yield the compound 30.

Production Process 17

The compound (I)-c can be produced by oxidizing the alcohol 30 producedin Production Process 15 into the aldehyde 35, subjecting the aldehyde35 to a Wittig reaction to yield the ester 36, converting the ester 36into the carboxylic acid 37, and amidating the carboxylic acid 37.Oxidizing agents for oxidizing the alcohol 30 include, for example,manganese dioxide, sulfur trioxide-pyridine complex,N-methylmorpholine-N-oxide, and chromic acid oxidizing agents. Theoxidation can also be performed by Swern oxidation or Moffat oxidation.Solvents for use herein can be any solvents that are not involved in thereaction and include, for example, halogenated hydrocarbons such asdichloromethane or chloroform, as well as ethyl acetate, acetonitrile,dimethyl sulfoxide, and dimethylformamide. A reaction temperature isgenerally from −78° C. to the reflux temperature of the solvent.Reagents for the Wittig reaction of the aldehyde 30 include, forexample, triethyl phosphonoacetate, ethyl diphenylphosphonoacetate, and(carbethoxymethyl)triphenylphosphonium bromide. Bases for use hereininclude, but are not specifically limited to, sodium hydride, sodiumhydrogencarbonate, potassium carbonate, sodium hydroxide, potassiumtert-butoxide, and benzyltrimethylammonium hydroxide. Solvents for useherein are not specifically limited, as long as they are inert to thereaction and include, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbonssuch as dichloromethane or chloroform, as well as ethyl acetate,acetonitrile, toluene, dimethyl sulfoxide, and dimethylformamide. Areaction temperature is generally from 0° C. to room temperature. Byhydrolyzing the ester 36 according to the procedure of ProductionProcess 12, the protecting group at the 1-position is concurrentlydeprotected, and the carboxylic acid 37 can thereby be produced. Thecompound (I)-c can be produced by amidating the carboxylic acid 37according to the procedure of Production Process 12.

Production Process 18

The compound (I)-d can be produced by hydrogenating the carboxylic acid37 produced in Production Process 17, and amidating the resultingcompound. Hydrogenation reagents for the olefin moiety of the carboxylicacid 37 include, but are not specifically limited to, palladium-carbon,platinum oxide, and palladium hydroxide-carbon. The pressure of hydrogenis from 1 to 5 atom. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction and include, forexample, ether solvents such as diethyl ether, tetrahydrofuran, dioxaneor dimethoxyethane, halogenated hydrocarbons such as dichloromethane,chloroform, as well as ethyl acetate, acetonitrile, toluene, anddimethylformamide. A reaction temperature is generally from roomtemperature to the reflux temperature of the solvent. The compound (I)-dcan be produced by amidating the carboxylic acid 38 according to theprocedure of Production Process 12.

Production Process 19

The compound (I)-e can be produced by halogenating the 3-position of thecompound 39 into the compound 40, protecting the 1-position of thecompound 40 to yield the compound 41, subjecting the compound 41 toSuzuki coupling with an arylboronic acid to yield the compound 42,reducing the compound 42 into the aniline 43, amidating the aniline 43into the compound 44, and deprotecting the 1-position. Halogenationreagents for the 3-position of the compound 39 include, for example,N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide, and bromine.Where necessary, a radical reaction initiator such as2,2′-azobisisobutyronitrile and benzoyl peroxide can be added. Theamount of the halogenation reagent is from 1.05 to 1.2 equivalents tothe raw material. Solvents for use herein are not specifically limited,as long as they are inert to the reaction, and include, for example,halogenated hydrocarbons such as dichloromethane, chloroform or carbontetrachloride, as well as ethyl acetate, acetonitrile, dimethylsulfoxide, and dimethylformamide. A reaction temperature is generallyfrom room temperature to the reflux temperature of the solvent.Protecting groups for the 1-position of the compound 40 include, forexample, tert-butyloxycarbonyl group, p-toluenesulfonyl group, andtriphenylmethyl group. The tert-butyloxycarbonyl group andp-toluenesulfonyl group can be introduced by allowing the compound 40 toreact with di-tert-butyl dicarbonate or p-toluenesulfonyl chloride inthe presence of a base. Such bases are not specifically limited, andpreferred examples thereof are triethylamine and4-N,N-dimethylaminopyridine. Solvents for use herein are notspecifically limited, as long as they are inert in the reaction, andinclude, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbonssuch as dichloromethane or chloroform, as well as pyridine, ethylacetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide. Areaction temperature is generally from 0° C. to the reflux temperatureof the solvent. The triphenylmethyl group can be introduced by allowingthe compound 40 to react with chlorotriphenylmethane in the presence ofa base. Such bases include, but are not specifically limited to, sodiumhydride, potassium tert-butoxide, lithium diisopropylamide, potassiumcarbonate, and sodium hydroxide. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction andinclude, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, as well as ethyl acetate,acetonitrile, dimethyl sulfoxide, and dimethylformamide. A reactiontemperature is from −20° C. to the reflux temperature of the solvent.Among arylboronic acids for use in Suzuki coupling of the compound 41,those commercially available will be purchased, and those notcommercially available can be easily prepared according to the procedureof Production Process 3. The amount of the arylboronic acid is from 1 to3 equivalents to the raw material. Catalysts for use herein include, forexample, palladium(II) acetate,dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0). The amount of the catalyst isabout 5% by mole relative to the raw material. Where necessary, aphosphine ligand in an amount of two times by mole that of the catalystcan be added. Such phosphine ligands include, for example,tri-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl,2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine. Examples ofbases for use herein are sodium hydrogencarbonate, sodium carbonate,potassium carbonate, cesium carbonate, and potassium fluoride. Solventsfor use herein are not specifically limited, as long as they do notadversely affect the reaction, and include, for example,dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, and toluene. A reaction temperature isgenerally from room temperature to the reflux temperature of thesolvent. The nitro group of the compound 42 is reduced, for example, byhydrogenation by catalysis of palladium-carbon, palladiumhydroxide-carbon, platinum oxide, or Raney's nickel, as well asreduction with tin(II) chloride, and reduction with iron-ammoniumchloride. Solvents for use in the hydrogenation are not specificallylimited, as long as they do not adversely affect the reaction, andinclude, for example, alcohol solvents such as methanol or ethanol,halogen-containing solvents such as methylene chloride or chloroform,ether solvents such as tetrahydrofuran or diethyl ether, as well asethyl acetate, dimethylformamide, and toluene. The amount of thehydrogenation catalyst is from 5% to 20% by weight relative to the rawmaterial. The pressure of hydrogen is generally from 1 to 5 atom. Areaction temperature is generally from room temperature to the refluxtemperature of the solvent. Solvents for use in the reduction withtin(II) chloride include, for example, alcohol solvents such as methanolor ethanol, halogenated hydrocarbon solvents such as methylene chlorideor chloroform, as well as dimethylformamide, N-methylpyrrolidone, andtoluene. A reaction temperature is generally from room temperature tothe reflux temperature of the solvent. Solvents for use in the reductionwith iron-ammonium chloride are preferably alcohol solvents such asaqueous methanol or aqueous ethanol. The amount of iron is from 3 to 10equivalents to the raw material. The amount of the ammonium chloride isfrom 10% to 20% by weight relative to the raw material. A reactiontemperature is generally the reflux temperature of the solvent. Theaniline 43 can be amidated by treating with a carboxylic acid and acondensing agent. Such condensing agents include, for example,dicyclohexylcarbodiimide, diisopropylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Wherenecessary, 1-hydroxybenzotriazole and/or N-hydroxysuccinimide can beadded. Solvents for use herein can be any solvents that are not involvedin the reaction and include, for example, halogen-containing solventssuch as methylene chloride or chloroform, ether solvents such as etheror tetrahydrofuran, as well as ethyl acetate, dimethylformamide, andtoluene. A reaction temperature is generally from room temperature tothe reflux temperature of the solvent. The aniline 43 can also beamidated by allowing the aniline 43 to react with an acid chloride inthe presence of a base. Such bases include, but are not specificallylimited to, triethylamine, diisopropylethylamine, and pyridine. Solventsfor use herein can be any solvents that are not involved in the reactionand include, for example, halogen-containing solvents such as methylenechloride or chloroform, ether solvents such as ether or tetrahydrofuran,as well as ethyl acetate, and toluene. A reaction temperature isgenerally from −78° C. to the reflux temperature of the solvent. Thetert-butyloxycarbonyl group and triphenylmethyl group as the protectinggroup of the amide 44 can be easily deprotected or removed by using anacid. Such acids include, for example, hydrochloric acid, sulfuric acid,and trifluoroacetic acid. Where necessary, a radical scavenger such asthiophenol and tri-iso-propylsilane can be added. Solvents for useherein are not specifically limited, as long as they are inert to thereaction, and include, for example, halogenated hydrocarbons such asdichloromethane or chloroform, alcohol solvents such as methanol orethanol, as well as anisole. A reaction temperature is generally from−20° C. to the reflux temperature of the solvent. Thetert-butyloxycarbonyl group and p-toluenesulfonyl group as theprotecting agent can be easily deprotected by using a base. Such basesinclude, but are not specifically limited to, aqueous sodium hydroxideand aqueous potassium hydroxide. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, alcohol solvents such as methanol or ethanol,ether solvents such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane. A reaction temperature is from room temperature to thereflux temperature of the solvent.

Production Process 20

The compound (I)-e can also be produced by deprotecting or removing, bythe procedure of Production Process 19, the protecting group of theaniline 43 produced in Production Process 19 to yield the compound 45,and amidating the compound 45 according to the amidation procedure usinga condensing agent as in Production Process 19.

Production Process 21

The aniline 45 can also be produced by subjecting the nitro derivative40 having a non-protected 1-position produced in Production Process 19to Stille coupling to yield the compound 46, and reducing the nitrogroup. Among aryltrialkyltins for use in the Stille coupling of thenitro derivative 40, those commercially available will be purchased, andthose not commercially available can be easily prepared according to theprocedure of Production Process 5. The amount of the aryltrialkyltin isfrom 1 to 3 equivalents to the raw material. Catalysts for use hereininclude, for example, palladium(II) acetate,dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0). The amount of the catalyst isabout 5% by mole relative to the raw material. Where necessary, aphosphine ligand in an amount of two times by mole that of the catalystcan be added. Such phosphine ligands include, for example,tri-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl,2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine. Solvents foruse herein are not specifically limited, as long as they do notadversely affect the reaction, and include, for example,dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane,diethylene glycol dimethyl ether, toluene, and xylenes. A reactiontemperature is generally from room temperature to the reflux temperatureof the solvent. By reducing the nitro derivative 46 according to theprocedure of Production Process 19, the aniline 45 can be produced.

Production Process 22

The compound 42 can also be produced by introducing, according to theprocedure of Production Process 19, a protecting group into the compound46 produced in Production Process 21.

Production Process 23

The compound (I)-f can be produced by alkylating the amide 44 producedin Production Process 19 to yield the N-alkylamide 47, and deprotectingthe N-alkylamide 47. The amide 44 can be alkylated by allowing the amide44 to react with a halogenalkyl in the presence of a base. Such basesinclude, but are not specifically limited to, sodium hydride, potassiumcarbonate, potassium tert-butoxide, and potassium hydroxide. Solventsfor use herein are not specifically limited, as long as they do notadversely affect the reaction, and include, for example, ether solventssuch as ether, tetrahydrofuran or dioxane, as well as dimethylformamide,dimethyl sulfoxide, and toluene. A reaction temperature is generallyfrom 0° C. to the reflux temperature of the solvent. By deprotecting theN-alkylamide 47 according to the procedure of Production Process 19, thecompound (I)-f can be produced.

Production Process 24

The compound (I)-g can be produced by converting the aniline 43 producedin Production Process 19 into the sulfonamide 48, and deprotecting thesulfonamide 48. The aniline 43 can be converted into the sulfonamide byallowing the aniline 43 to react with a sulfonyl chloride in thepresence of a base. Such bases include, but are not specifically limitedto, triethylamine, 4-dimethylaminopyridine, potassium carbonate, sodiumhydride, and pyridine. The amount of the sulfonyl chloride is from 1.1to 1.5 equivalents to the raw material. Reaction solvents for use hereinare not specifically limited, as long as they do not adversely affectthe reaction and include, for example, halogenated hydrocarbons such asdichloromethane or chloroform, ether solvents such as ether,tetrahydrofuran or dioxane, as well as ethyl acetate, acetonitrile,dimethyl sulfoxide, toluene, and dimethylformamide. Among them, ether,tetrahydrofuran, dioxane, and other ether solvents are preferred. Areaction temperature is generally from 0° C. to room temperature. Bydeprotecting the sulfonamide 48 according to the procedure of ProductionProcess 19, the compound (I)-g can be produced.

Production Process 25

The compound (I)-g can also be produced by converting the aniline 45having a non-protected 1-position produced in Production Process 21 intoa sulfonamide according to the procedure of Production Process 24.

Production Process 26

The compound (I)-h can be produced by alkylating the sulfonamide 48produced in Production Process 24, and deprotecting the resultingcompound. The sulfonamide 48 can be alkylated by allowing thesulfonamide 48 to react with a halogenalkyl in the presence of a base.Such bases include, but are not specifically limited to, sodium hydride,potassium carbonate, potassium tert-butoxide, and triethylamine.Solvents for use herein are not specifically limited, as long as they donot adversely affect the reaction, and include, for example, ethersolvents such as ether, tetrahydrofuran or dioxane, as well asdimethylformamide, dimethyl sulfoxide, and toluene. A reactiontemperature is generally from 0° C. to the reflux temperature of thesolvent. By deprotecting the sulfonamide 49 according to the procedureof Production Process 19, the compound (I)-h can be produced.

Production Process 27

The compound (I)-i can be produced by subjecting the indazole 50 tohalogenation and introduction of a protecting group according to theprocedure of Production Process 19 to yield the compound 52, allowingthe compound 52 to react with chlorosulfuric acid to yield sulfonylchloride 53, converting the sulfonyl chloride 53 into the sulfonamide54, subjecting the sulfonamide 54 to Suzuki coupling to yield thecompound 55, and deprotecting the compound 55. The sulfonyl chloride 53can be obtained by allowing the halogenated compound 52 to react with 1to 2 equivalents of chlorosulfuric acid. Solvents for use herein are notspecifically limited, as long as they do not adversely affect thereaction, and include, for example, halogen-containing solvents such asmethylene chloride or chloroform. A reaction temperature is generallyfrom 0° C. to room temperature. The sulfonyl chloride 53 can besulfonamidated by allowing the sulfonyl chloride 53 to react with anamine in the presence of a base. An excess amount of the amine can serveas the base. Alternatively, for example, triethylamine,4-dimethylaminopyridine, potassium carbonate, and sodium hydride can beadded as the base. Reaction solvents for use herein are not specificallylimited, as long as they do not adversely affect the reaction, andinclude, for example, halogenated hydrocarbons such as dichloromethaneor chloroform, ether solvents such as ether, tetrahydrofuran or dioxane,as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, toluene, anddimethylformamide. A reaction temperature is generally from 0° C. toroom temperature. The sulfonamide 54 is subjected to Suzuki couplingwith an arylboronic acid according to the procedure of ProductionProcess 19 to thereby yield the compound 55. The compound 55 is thendeprotected according to the procedure of Production Process 19 tothereby yield the compound (I)-i.

Production Process 28

The compound (I)-j can be produced by converting the halide or sulfonateproduced in Production Process 15 into an azide, reducing the azide intothe amine 57, deprotecting the amine 57 to yield the compound 58, andamidating the compound 58. The azide 56 can be obtained by allowing thecompound 31 to react with sodium azide or potassium azide. Reactionsolvents for use herein are not specifically limited, as long as they donot adversely affect the reaction, and include, for example, alcoholsolvents such as methanol or ethanol, ether solvents such as diethylether, tetrahydrofuran, dioxane or dimethoxyethane, as well as dimethylsulfoxide, and dimethylformamide. A reaction temperature is generallyfrom −20° C. to the reflux temperature of the solvent. The azide 56 canbe reduced, for example, by hydrogenation by catalysis ofpalladium-calcium carbonate, palladium-carbon, palladiumhydroxide-carbon, platinum oxide, and Raney nickel. Solvents for use inthe hydrogenation are not specifically limited, as long as they do notadversely affect the reaction, and include, for example, alcoholsolvents such as methanol or ethanol, halogen-containing solvents suchas methylene chloride or chloroform, ether solvents such astetrahydrofuran or diethyl ether, as well as ethyl acetate,dimethylformamide, and toluene. The amount of the hydrogenation catalystis from 5% to 20% by weight relative to the raw material. The pressureof hydrogen is generally normal pressure (atmospheric pressure) but canbe increased up to 5 atm. A reaction temperature is generally from roomtemperature to the reflux temperature of the solvent. The 1-position ofthe amine 57 is deprotected according to the procedure of ProductionProcess 3 to thereby yield the compound 58. Then, the compound 58 isamidated according to the procedure of Production Process 19 using acondensing agent to thereby yield the compound (I)-j.

Production Process 29

The compound 58 obtained in Production Process 28 can also be producedby reducing the nitrile 28 produced in Production Process 14. Reducingagents for use herein include, for example, sodium borohydride, lithiumaluminium hydride, and aluminium hydride. Where necessary, an additivesuch as aluminium trichloride, boron trifluoride, cobalt chloride, andRaney nickel can be added. Reaction solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, alcohol solvents such as methanol or ethanol,ether solvents such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane. A reaction temperature is from −78° C. to the refluxtemperature of the solvent. Production Process 30

The compound (I)-k can be produced by converting the sulfonate or halide31 obtained in Production Process 15 into the amine 59, and deprotectingthe amine 59. The sulfonate or halide 31 can be aminated to react withan amine in the presence of a base. An excess amount of the amine canserve as the base. Alternatively, a base such as sodium hydride,potassium carbonate, and potassium tert-butoxide can be added. Solventsfor use herein are not specifically limited, as long as they do notadversely affect the reaction, and include, for example, alcoholsolvents such as methanol or ethanol, halogen-containing solvents suchas methylene chloride or chloroform, ether solvents such astetrahydrofuran or diethyl ether, as well as ethyl acetate,dimethylformamide, dimethyl sulfoxide, and toluene. A reactiontemperature is generally from 0° C. to the reflux temperature of thesolvent. By deprotecting the amine 59 according to the procedure ofProduction Process 3, the compound (I)-k can be produced.

Production Process 31

The compound (I)-l can be produced by allowing the sulfonate or halide31 obtained in Production Process 15 to react with an alcohol in thepresence of a base to thereby yield the ether 60, and deprotecting theether 60. Bases for use in the etherification of the sulfonate or halide31 include, but are not specifically limited to, sodium hydride,potassium carbonate, potassium tert-butoxide, and silver(I) oxide.Solvents for use herein are not specifically limited, as long as they donot adversely affect the reaction, and include, for example,halogen-containing solvents such as methylene chloride or chloroform,ether solvents such as tetrahydrofuran or diethyl ether, as well asethyl acetate, dimethylformamide, dimethyl sulfoxide, and toluene. Areaction temperature is generally from 0° C. to the reflux temperatureof the solvent. By deprotecting the ether 60 according to the procedureof Production Process 3, the compound (I)-l can be produced.

Production Process 32

The compound (I)-m can be produced by subjecting the alcohol 30 obtainedin Production Process 15 and an aryl alcohol to Mitsunobu reaction tothereby yield the aryl ether 61, and deprotecting the aryl ether 61. Thecompound 61 can be produced, for example, by allowing the alcohol 30 toreact with the aryl alcohol in the presence of triphenylphosphine anddiethyl azodicarboxylate or diisopropyl azodicarboxylate. Solvents foruse herein are not specifically limited, as long as they do notadversely affect the reaction, and include, for example,halogen-containing hydrocarbons such as methylene chloride orchloroform, ether solvents such as tetrahydrofuran, diethyl ether ordioxane, as well as ethyl acetate, dimethylformamide, and toluene. Areaction temperature is generally from 0° C. to room temperature. Bydeprotecting the compound 61 according to the procedure of ProductionProcess 3, the compound (I)-m can be produced.

Production Process 33

The compound (I)-n can be produced by allowing the aniline 43 obtainedin Production Process 19 to react with an isocyanate to yield the urea62, and deprotecting the urea 62. Solvents for use in the conversion ofthe aniline 43 into the urea are not specifically limited, as long asthey do not adversely affect the reaction, and include, for example,halogen-containing solvents such as methylene chloride or chloroform,ether solvents such as tetrahydrofuran or diethyl ether, as well asethyl acetate, dimethylformamide, dimethyl sulfoxide, and toluene. Areaction temperature is generally from 0° C. to the reflux temperatureof the solvent. By deprotecting the urea 62 according to the procedureof Production Process 19, the compound (I)-n can be produced.

Production Process 34

The compound (I)-o can be produced by allowing the aldehyde 35 obtainedin Production Process 17 to react with an alkyllithium, a Grignardreagent, a metal aryl, or a metal halogenoaryl to yield the alcohol 63,oxidizing the alcohol 63 into the ketone 64, and deprotecting the ketone64. The alkyllithium for the reaction of the aldehyde 35 is commerciallyavailable. The Grignard reagent can be prepared by using an alkyl halideand magnesium. Among metal aryls or metal halogenoaryls for use herein,those commercially available will be purchased, and those notcommercially available can be easily prepared according to the procedureof Production Process 3. Reaction solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene, andtoluene. A reaction temperature is from −78° C. to room temperature.Oxidizing agents for oxidizing the alcohol 63 include, for example,manganese dioxide, sulfur trioxide-pyridine complex,N-methylmorpholine-N-oxide, and chromic acid oxidizing agents. Theoxidation can also be performed by Swern oxidation or Moffat oxidation.Solvents for use herein can be any solvents that are not involved in thereaction and include, for example, halogenated hydrocarbons such asdichloromethane or chloroform, as well as ethyl acetate, acetonitrile,dimethyl sulfoxide, and dimethylformamide. A reaction temperature isgenerally from −78° C. to the reflux temperature of the solvent. Bydeprotecting the ketone 64 according to the procedure of ProductionProcess 3, the compound (I)-o can be produced.

Production Process 35

The compound 27 obtained in Production Process 14 can also be producedby treating the fluorobenzene 65 with, for example, lithium amide toyield a lithium aryl, allowing the lithium aryl to react with an arylaldehyde to yield the alcohol 66, oxidizing the alcohol 66 into aketone, and replacing T² a with cyano group.

Lithium amides for converting the fluorobenzene 65 into the lithium arylinclude, for example, lithium diisopropylamide, and lithium2,2,6,6-tetramethylpiperidide. Reaction solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andpreferred examples thereof are ether solvents such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene, andtoluene. A reaction temperature is from −78° C. to room temperature. Byoxidizing the alcohol 66 according to the procedure of ProductionProcess 12, the compound 67 can be produced. Reagents for converting thecompound 67 into the nitrile 27 include zinc cyanide, lithium cyanide,sodium cyanide, or potassium cyanide in combination with a transitionmetal catalyst such as tetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium,dichlorobis(triphenylphosphine)palladium, and palladium diacetate. Thereaction may be performed in the presence of a catalytic amount ofcopper iodide or a phosphine ligand such as triphenylphosphine and1,1′-bis(diphenylphosphino)ferrocene. Preferred examples of solvents foruse herein are dimethylformamide, N-methylpyrrolidone, propionitrile,and acetonitrile. A reaction temperature is preferably within a rangefrom 80° C. to 150° C. The nitrile 27 can also be produced by allowingthe compound 67 to react with copper cyanide in a solvent such asdimethylformamide or N-pyrrolidone at a temperature within a range from140° C. to 200° C.

Production Process 36

The carboxylic acid 23 obtained in Production Process 12 can also beproduced by treating the compound 67 obtained in Production Process 35with hydrazine to yield the indazole 68, converting the indazole 68 intoa lithium aryl with the use of an alkyl lithium, and allowing thelithium aryl to react with carbon dioxide.

By closing the indazole ring of the compound 67 with the use ofhydrazine monohydrate according to the procedure of Production Process12, the indazole 68 can be produced. The alkyllithium for converting theindazole 68 into the lithium aryl includes, for example, n-butyllithium,sec-butyllithium, tert-butyllithium, and phenyllithium. Where necessary,an additive such as N,N,N′,N′-tetramethylethylenediamine orhexamethylphosphoramide can be added.

By allowing the lithium aryl to react with carbon dioxide gas or dryice, the carboxylic acid 23 can be produced. Reaction solvents for useherein are not specifically limited, as long as they are inert to thereaction, and preferred examples thereof are ether solvents such asdiethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well asbenzene, and toluene. A reaction temperature is from −78° C. to roomtemperature.

Production Process 37

The aniline 43 obtained in Production Process 19 can also be produced byprotecting the 1-position of the carboxylic acid 23 obtained inProduction Process 12 to yield the compound 69, subjecting the compound69 to Curtius rearrangement to yield the carbamate 70, and deprotectingthe carbamate.

By introducing a protecting group into the 1-position according to theprocedure of Production Process 15, the compound 69 can be produced. Thecompound 69 can be subjected to Curtius rearrangement by treating thecompound 69 with, for example, diphenylphosphoryl azide and an aminesuch as triethylamine or diisopropylethylamine to yield an isocyanate,and allowing the isocyanate to react with an alcohol, or by treating thecompound 69 with, for example, thionyl chloride or oxalyl chloride toyield an acid chloride, treating the acid chloride with lithium azide,sodium azide or potassium azide to yield an isocyanate, and allowing theisocyanate to react with an alcohol. The alcohol for use herein is notspecifically limited, of which benzyl alcohol and tert-butanol areespecially preferred. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction, and include, forexample, toluene, benzene, tetrahydrofuran, and dioxane. A reactiontemperature is generally from room temperature to the reflux temperatureof the solvent. A tert-butyloxycarbonyl group as the protecting group ofthe carbamate 70 can be easily deprotected or removed by using an acid.Such acids include, for example, hydrochloric acid, sulfuric acid, andtrifluoroacetic acid. Where necessary, a radical scavenger such asthiophenol or tri-iso-propylsilane can be added. Solvents for use hereinare not specifically limited, as long as they are inert in the reaction,and include, for example, halogenated hydrocarbons such asdichloromethane or chloroform, as well as anisole. A benzyloxycarbonylgroup as the protecting group can be easily deprotected or removed byhydrogenation. Reagents for use in the hydrogenation include, but arenot specifically limited to, palladium-carbon, platinum oxide, andpalladium hydroxide-carbon. The pressure of hydrogen is from 1 to 5 atm.Solvents for use herein are not specifically limited, as long as theyare inert to the reaction, and include, for example, ether solvents suchas diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane,halogenated hydrocarbons such as dichloromethane or chloroform, as wellas ethyl acetate, acetonitrile, toluene, and dimethylformamide. Areaction temperature is generally from room temperature to the refluxtemperature of the solvent.

Production Process 38

The aniline 43 obtained in Production Process 19 can also be produced byprotecting the 1-position of the compound 68 obtained in ProductionProcess 36 to yield the compound 71, and then aminating T².

By introducing a protecting group into the 1-position of the compound 68according to the procedure of Production Process 15, the compound 71 canbe produced. Palladium catalysts for use in amination of the compound 71include, for example, tris(dibenzylideneacetone)dipalladium, andpalladium diacetate. Phosphine ligands for use herein include, forexample, 2,2′-bis(diphenylphosphino)-1,1′-naphthyl,1,1′-bis(diphenylphosphino)ferrocene, and tri(tert-butyl)phosphine.Bases for use herein include, for example, sodium tert-butoxide,potassium tert-butoxide, and cesium carbonate. An ammonia equivalent foruse herein is not specifically limited and is preferablybenzophenoneimine. Acids for use in hydrolysis of the resulting iminederivative include, but are not specifically limited to, dilutedhydrochloric acid and diluted sulfuric acid. Solvents for use in thereaction are not specifically limited, as long as they are inert to thereaction, and include, for example, toluene, tetrahydrofuran, dioxane,and dimethoxyethane. A reaction temperature is generally from roomtemperature to 120° C.

Production Process 39

The compound (I)-e can also be produced by combining, with a resin, the1-position of the compound 40 obtained in Production Process 19 to yieldthe compound 72, subjecting the product to Suzuki coupling with anarylboronic acid to yield the compound 73, reducing the product into theaniline 74, amidating the product into the compound 75, and thenexciding the target compound from the resin using an acid. Advantages ofthe synthesis using a resin are that a multitude of a target compoundcan be synthetically prepared at once, that a purification procedure ineach step is not required, as an excess reagent can be removed bywashing, and that the resin itself serves as a protecting group. Byallowing the compound 40 to react with the resin in the presence of abase, 72 can be obtained. Such bases include, but are not specificallylimited to, triethylamine, diisopropylethylamine,4-N,N-dimethylaminopyridine, sodium hydride, potassium tert-butoxide,and potassium carbonate. Solvents for use herein are not specificallylimited, as long as they are inert to the reaction and can hold affinityfor the resin, and include, for example, ether solvents tetrahydrofuranor dioxane, as well as dimethyl sulfoxide, dimethylformamide,N-methylpyrrolidone, ethyl acetate, and acetonitrile. A reactiontemperature is generally from 0° C. to the reflux temperature of thesolvent. Among arylboronic acids for use in Suzuki coupling of thecompound 72, those commercially available will be purchased, and thosenot commercially available can be easily prepared according to theprocedure of Production Process 3. The arylboronic acid is used inexcess. Catalysts for use herein include, for example, palladium(II)acetate, dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0). The amount of the catalyst isabout 5% by mole relative to the arylboronic acid. Where necessary, aphosphine ligand in an amount of two times by mole that of the catalystcan be added. Such phosphine ligands include, for example,tri-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl,2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine. Bases for useherein include, for example, sodium hydrogencarbonate, sodium carbonate,potassium carbonate, cesium carbonate, and potassium fluoride. Solventsfor use herein are not specifically limited, as long as they are inertto the reaction and can hold affinity for the resin, and include, forexample, dimethylformamide, N-methylpyrrolidone, tetrahydrofuran,dioxane, and diethylene glycol dimethyl ether. A reaction temperature isgenerally from room temperature to the reflux temperature of thesolvent. The nitro group of the compound 73 can be reduced, for example,by reduction with tin(II) chloride or reduction with iron-ammoniumchloride. Solvents for use in the reduction with tin(II) chlorideinclude, for example, alcohol solvents such as methanol or ethanol,dimethylformamide, and N-methylpyrrolidone. A reaction temperature isgenerally from room temperature to the reflux temperature of thesolvent. Solvents for use in the reduction with iron-ammonium chlorideare preferably alcohol solvents such as aqueous methanol or aqueousethanol. The amount of iron is from 3 to 10 equivalents to the rawmaterial. The amount of the ammonium chloride is from 10% to 20% byweight relative to the raw material. A reaction temperature is generallythe reflux temperature of the solvent. The aniline 74 can be amidated bytreating with a carboxylic acid and a condensing agent. Such condensingagents include, for example, dicyclohexylcarbodiimide,diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Wherenecessary, 1-hydroxybenzotriazole and/or N-hydroxysuccinimide can beadded. Solvents for use herein are not specifically limited, as long asthey are inert to the reaction and can hold affinity for the resin, andinclude, for example, ether solvents such as tetrahydrofuran or dioxane,as well as dimethylformamide, N-methylpyrrolidone, and ethyl acetate. Areaction temperature is generally from room temperature to the refluxtemperature of the solvent. The compound (I)-e can be easily excidedfrom the resin using an acid. Such acids include, for example,hydrochloric acid, sulfuric acid, and trifluoroacetic acid. Wherenecessary, a radical scavenger such as thiophenol ortri-iso-propylsilane can be added. Solvents for use herein are notspecifically limited, as long as they are inert to the reaction, andinclude, for example, halogenated hydrocarbons such as dichloromethaneor chloroform. A reaction temperature is from room temperature to thereflux temperature of the solvent.

Production Process 40

The compound (I)-g can also be produced by converting the aniline 74obtained in Production Process 39 into the sulfonamide 76, and thenexciding the target compound from the resin using an acid. The aniline74 can be converted into the sulfonamide by allowing it to react with asulfonyl chloride in the presence of a base. Such bases include, but arenot specifically limited to, triethylamine, 4-dimethylaminopyridine,potassium carbonate, and sodium hydride. The amount of the base is from0.9 to 1.1 equivalents to the sulfonyl chloride. Reaction solvents foruse herein are not specifically limited, as long as they are inert tothe reaction and can hold affinity for the resin, and include, forexample, ether solvents such as tetrahydrofuran or dioxane, as well asdimethyl sulfoxide, N-methylpyrrolidone, dimethylformamide, ethylacetate, and acetonitrile. Among them, ether solvents such astetrahydrofuran or dioxane are preferred. A reaction temperature isgenerally from 0° C. to room temperature. By exciding from the resinaccording to the procedure of Production Process 39, the compound (I)-gcan be produced.

Material compounds for use in the production of the compounds of thepresent invention can be in the form of salts and/or hydrates and arenot specifically limited as long as they do not adversely affect thereactions. When the compounds (I) according to the present invention areobtained as free compounds, they can be converted into acceptable saltsof the above-mentioned compound (I) according to a conventionalprocedure. Various isomers such as geometrical isomers, optical isomersdue to an asymmetric carbon, stereoisomers, and tautomers obtained asthe compounds (I) according to the present invention can be purified andisolated according to a conventional separation means. Such separationmeans include, for example, recrystallization, diastereomeric saltmethod, enzymatic resolution, and a variety of chromatography such asthin layer chromatography, column chromatography or gas chromatography.

The term “salt(s)” as used in the present description is notspecifically limited, as long as it can form a salt with the compoundaccording to the present invention and is pharmacologically acceptable.Preferred examples of the salts are hydrohalides such as hydrofluorides,hydrochlorides, hydrobromides or hydroiodides; salts of inorganic acids,such as sulfates, nitrates, perchlorates, phosphates, carbonates orbicarbonates; salts of organic carboxylic acids, such as acetates,trifluoroacetates, oxalates, maleates, tartrates, fumarates or citrates;salts of organic sulfonic acids, such as methanesulfonates,trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates,toluenesulfonates or camphorsulfonates; salts of amino acids, such asaspartates or glutamates; quaternary amine salts; alkali metal saltssuch as sodium salts or potassium salts; alkaline earth metal salts suchas magnesium salts or calcium salts. More preferred examples of the“pharmacologically acceptable salt(s)” are hydrochlorides, oxalates andtrifluoroacetates.

The compounds represented by the formula (I) according to the presentinvention, a salt thereof or a hydrate of them can be formulated intopharmaceutical preparations according to a conventional procedure.Preferred dosage forms are tablets, powders, fine granules, granules,coated tablets, capsules, syrups, troches, inhalants, suppositories,injections, ointments, ophthalmic ointments, eye drops, nasal drops, eardrops, cataplasms, and lotions. In the formulation, generally usedfillers, binders, disintegrators, lubricants, coloring agents, andflavoring agents, as well as stabilizers, emulsifiers, absorbefacients,surfactants, pH adjusting agents, antiseptics, and antioxidantsaccording to necessity can be used. They can be formulated according toa conventional procedure using components generally used as rawmaterials for pharmaceutical preparations. Examples of such componentsinclude (1) animal or vegetable oils such as soybean oil, beef tallow orsynthetic glycerides; (2) hydrocarbons such as liquid paraffins,squalane or solid paraffins; (3) ester oils such as octyldodecylmyristate or isopropyl myristate; (4) higher alcohols such ascetostearyl alcohol or behenyl alcohol; (5) silicon resins; (6) siliconoils; (7) surfactants such as polyoxyethylene fatty acid esters,sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene hydrogenated castor oils orpolyoxyethylene-polyoxypropylene block copolymers; (8) water-solublepolymers such as hydroxyethyl cellulose, poly(acrylic acid)s,carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone ormethylcellulose; (9) lower alcohols such as ethanol or isopropanol; (10)polyhydric alcohols such as glycerol, propylene glycol, dipropyleneglycol or sorbitol; (11) sugars such as glucose or sucrose; (12)inorganic powders such as silicic anhydride, magnesium aluminiumsilicate or aluminium silicate; and (13) purified water.

1) The fillers include, for example, lactose, corn starch, sucrose,glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide;2) the binders include, for example, polyvinyl alcohol, polyvinyl ether,methylcellulose, ethylcellulose, gum arabic, gum tragacanth, gelatin,shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene blockpolymers, meglumine, calcium citrate, dextrin, and pectin; 3) thedisintegrators include, for example, starch, agar, gelatin powder,crystalline cellulose, calcium carbonate, sodium hydrogencarbonate,calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium; 4)the lubricants include, for example, magnesium stearate, talc,polyethylene glycol, silica, and hardened vegetable oils; 5) thecoloring agents can be any coloring agents which are approved to add topharmaceutical preparations; 6) the flavoring agents include, forexample, cocoa powder, menthol, aromatic powder, peppermint oil,borneol, and cinnamon powder; 7) the antioxidants can be anyantioxidants which are approved to add to pharmaceutical preparationssuch as ascorbic acid or α-tocopherol.

1) As oral preparations, the compound according to the present inventionor the salt thereof is compounded with a filler, and if necessary, abinder, disintegrator, lubricant, coloring agent, flavoring agent, andother components, and the resulting mixture is formulated according to aconventional procedure into a powder, fine granules, granules, tablet,coated tablet, capsule, etc. 2) The tablets and granules can beappropriately coated with, for example, sugar or gelatin, or otheraccording to necessity. 3) Liquid formulations such as syrups, injectionpreparations or eye droppers can be prepared in a conventional method,by adding a pH adjusting agents, solubilizer, and isotonizing agent, andif necessary, a solubilizing agent, stabilizer, buffer, suspendingagent, antioxidant, and other components. The liquid formulations canalso be formed into freeze-dried products. The injections can beadministered intravenously, subcutaneously and/or intramuscularly.Preferred examples of the suspending agents are methylcellulose,polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder,sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate;preferred examples of solubilizers are polyoxyethylene hardened casteroil, polysorbate 80, nicotinamide, and polyoxyethylene sorbitanmonolaurate; preferred examples of the stabilizers are sodium sulfite,sodium metasulfite, and ether; preferred examples of the preservativesare methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid,phenol, cresol, and chlorocresol. 4) External preparations can beproduced according to a conventional procedure not specifically limited.Base materials for use herein can be any raw materials generally usedin, for example, pharmaceutical preparations, quasi drugs, andcosmetics. Such raw materials include, for example, animal or vegetableoils, mineral oils, ester oils, waxes, higher alcohols, fatty acids,silicon oils, surfactants, phospholipids, alcohols, polyhydric alcohols,water-soluble polymers, clay minerals, and purified water. If necessary,any of pH adjusting agents, antioxidants, chelating agents, antisepticsand antimolds, coloring agents, and flavors can be added. In addition,components having differentiation-inducing action, blood-flowaccelerators, bactericides, anti-inflammatory agents, cell activators,vitamins, amino acids, humectants, keratolytic agents, and othercomponents can be added according to necessity.

The dose of the pharmaceutical preparation according to the presentinvention varies depending on the degree of symptom, age, sex, bodyweight, administration mode, type of the salt, difference in sensibilityto the drug, concrete type of the disease, and other factors. Generally,in oral administration, the pharmaceutical preparations may beadministered at a daily dose of about 30 μg to about 1000 mg, preferablyabout 100 μg to about 500 mg, and more preferably about 100 μg to about100 mg for an adult in one to several divided doses. In injectionadministration, they may be administered at a daily dose of about 1 toabout 3000 μg/kg, and preferably about 3 to about 1000 μg/kg for anadult in one to several divided doses.

The present invention can provide novel indazole compounds. Thecompounds (I) according to the present invention or the salts thereofhave excellent inhibitory action on c-Jun amino-terminal kinases,especially on JNK 3. Accordingly, the compounds (I) according to thepresent invention or the salts thereof, and pharmaceutical compositionscontaining the same are useful as therapeutic agents or prophylacticagents for an immunologic disease, inflammatory disease and/orneurodegenerative disease. They are particularly useful as therapeuticagents or prophylactic agents, for example, for acute neurodegenerativediseases such as acute stage of cerebrovascular disorder, head injury,spinal code injury, neuropathy due to hypoxia, and neuropathy due tohypoglycemia; chronic neurodegenerative diseases such as Alzheimer'sdisease, Parkinson's disease, Huntington's chorea, amyotrophic lateralsclerosis, multiple sclerosis or spinocerebellar degeneration; epilepsy;hepatic encephalopathy; peripheral neuropathy; Parkinsonian syndrome;spastic paralysis; pain; neuralgia; infectious encephalomyelitis;cerebrovascular dementia; or dementia or neurological symptom due tomeningitidis.

EXAMPLES

The following production examples, examples, and test examples areindicated by illustration, and the compounds of the present inventionare never restricted by the following examples. Those skilled in the artcan modify not only the following examples but also the claims accordingto the present description in various ways to exert the most of thepresent invention, and such modifications and variations are alsoincluded within the scope of the appended claims relating to the presentdescription.

Production Example I-1-a4-Fluoro-3-[(3-fluorophenyl)(hydroxy)methyl]benzonitrile

In an atmosphere of nitrogen gas, 76.3 ml of 1.56 M solution ofn-butyllithium in hexane was added to a solution of 11.1 g ofN,N-diisopropylamine in 200 ml tetrahydrofuran under ice-cooling, andthe mixture was stirred at the same temperature for 15 minutes. Aftercooling to −78° C., a solution of 12.1 g of 4-fluorobenzonitrile in 40ml tetrahydrofuran was added dropwise. After stirring at the sametemperature for 45 minutes, 10.6 ml of 3-fluorobenzaldehyde was addeddropwise. After stirring at the same temperature for 25 minutes,saturated aqueous ammonium chloride solution was added and the solventwas removed. To the residue was added 150 ml of ethyl acetate, and themixture was sequentially washed with 1 N hydrochloric acid, water,saturated aqueous sodium hydrogencarbonate solution and brine, driedover anhydrous magnesium sulfate and the solvent was evaporated. Thecrude product was purified and separated by silica gel columnchromatography (ethyl acetate:toluene=3:97 to 1:19), and the resultingcrystals were recrystallized from diisopropyl ether-hexane, to give 12.7g of the title compound as pale yellow needles.

¹H-NMR (400 MHz, DMSO-D₆) δ 5.97 (1H, d, J=4.4 Hz), 6.40 (1H, d, J=4.4Hz), 7.09 (1H, td, J=8.4, 2.8 Hz), 7.17 (1H, d, J=8.0 Hz), 7.21 (1H, d,J=10.0 Hz), 7.33-7.44 (2H, m), 7.86 (1H, m), 8.04 (1H, dd, J=2.0, 6.8Hz).

Production Example I-1-b 3-(3-Fluorophenyl)-1H-5-indazolecarbonitrile

To a solution of 12.5 g of4-fluoro-3-[(3-fluorophenyl)(hydroxy)methyl]benzonitrile in 200 mlmethylene chloride was added 43.8 g of activated manganese dioxide, andthe resulting mixture was stirred at room temperature for 10 hours andat 35° C. for further 9 hours. Then, the manganese dioxide was filteredoff through Celite. After removing the solvent by distillation, theresidue was dissolved in 25 ml of tetrahydrofuran and 25 ml of methanol.12 ml of hydrazine monohydrate was added, followed by stirring at roomtemperature for 7 hours. The reaction mixture was added with 150 ml ofwater, and ice-cooled. Then, the resulting crystals were collected byfiltration. The crystals were dried in vacuo, to give 11.6 g of thetitle compound as yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.30 (1H, td, J=8.0, 2.8 Hz), 7.58 (1H, td,J=8.0, 6.4 Hz), 7.75 (1H, dd, J=8.8, 1.6 Hz), 7.79 (1H, d, J=8.8 Hz),7.83 (1H, dd, J=10.4, 2.8 Hz), 7.93 (1H, d, J=8.0 Hz), 8.78 (1H, s),13.88 (1H, s).

Production Example I-1-c 3-(3-Fluorophenyl)-1H-5-indazolecarboxylic acid

To 10.0 g of 3-(3-fluorophenyl)-1H-5-indazolecarbonitrile weresequentially added 50 ml of glacial acetic acid, 15 ml of water and 12ml of concentrated sulfuric acid, and the mixture was stirred at 110° C.for 6.5 hours. After standing to cool, the reaction mixture was addedwith 150 ml of ice-water, and the resulting crystals were collected byfiltration. The resulting crystals were dried in vacuo, to give 10.7 gof the title compound as beige orange-pink crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.28 (1H, dt, J=2.8, 10.1 Hz), 7.61 (1H, dt,J=6.2, 8.2 Hz), 7.67 (1H, d, J=8.8 Hz), 7.72 (1H, ddd, J=1.5, 2.8, 10.1Hz), 7.82 (1H, d, J=8.2 Hz), 7.97 (1H, d, J=8.8 Hz), 8.63 (1H, s),12.80-12.95 (1H, bs), 13.67 (1H, s)

Production Example I-2-a 3-(3-Fluorophenyl)-1H-7-indazolecarbonitrile

A total of 637 mg of the title compound as yellow crystals was obtainedfrom 2.42 g of 2-fluorobenzonitrile by the procedures of ProductionExamples I-1a and I-1b.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.30 (1H, td, J=8.0, 2.4 Hz), 7.40 (1H, t,J=8.0 Hz), 7.60 (1H, td, J=8.0, 6.8 Hz), 7.77 (1H, d, J=10.0 Hz), 7.87(1H, d, J=8.0 Hz), 8.02 (1H, d, J=8.0 Hz), 8.49 (1H, d, J=8.0 Hz), 14.32(1H, s).

Production Example I-2-b 3-(3-Fluorophenyl)-1H-7-indazolecarboxylic acid

A total of 637 mg of the title compound as yellow crystals was obtainedfrom 593 mg of 3-(3-fluorophenyl)-1H-7-indazolecarbonitrile by theprocedure of Production Example I-1-c.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.28 (1H, td, J=8.0, 2.8 Hz), 7.36 (1H, dd,J=7.2, 8.0 Hz), 7.60 (1H, td, J=8.0, 6.8 Hz), 7.76 (1H, dd, J=10.0, 2.8Hz), 7.87 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.0 Hz), 8.39 (1H, d, J=8.0Hz), 13.40 (1H, s), 13.43 (1H, s).

Production Example I-3-a 3-Fluoro-2-(1,1,1-trimethylsilyl)benzonitrile

To a solution of 5.57 g of N,N-diisopropylamine in 100 mltetrahydrofuran at −30° C. in an atmosphere of nitrogen gas was added 33ml of 1.59 M solution of n-butyllithium in hexane, and the mixture wasstirred at the same temperature for 25 minutes. After cooling to −78°C., a solution of 6.06 g of 3-fluorobenzonitrile in 9 ml tetrahydrofuranwas added dropwise. After stirring at the same temperature for 1 hour,12.7 ml of chlorotrimethylsilane was added dropwise. After stirring atthe same temperature for 1 hour, saturated aqueous ammonium chloridesolution was added and the solvent was removed. The residue was addedwith 130 ml of ethyl acetate, and sequentially washed with water andbrine, and dried over anhydrous magnesium sulfate. After filtrating theorganic layer through a silica pat, the solvent was evaporated. Thecrude product was purified and separated by silica gel columnchromatography (hexane), to give 6.93 g of the title compound as a paleblue oil.

¹H-NMR (400 MHz, CDCl₃) δ 0.48 (9H, s), 7.21 (1H, ddd, J=1.2, 8.4, 9.2Hz), 7.42 (1H, ddd, J=5.6, 7.6, 8.4 Hz), 7.50 (1H, dd, J=1.2, 7.6 Hz).

Production Example I-3-b3-Fluoro-4-[(3-fluorophenyl)(hydroxy)methyl]-2-(1,1,1-trimethylsilyl)benzonitrile

In an atmosphere of nitrogen gas, 7.0 ml of 1.56 M n-butyllithium inhexane was added to a solution of 1.61 g of2,2,6,6-tetramethylpiperidine in 20 ml tetrahydrofuran underice-cooling, and the mixture was stirred at the same temperature for 1hour. After cooling to −78° C., a solution of 2.0 g of3-fluoro-2-(1,1,1-trimethylsilyl)benzonitrile in 5 ml tetrahydrofuranwas added dropwise. After stirring at the same temperature for 55minutes, 1.10 ml of 3-fluorobenzaldehyde was added dropwise. Afterstirring at the same temperature for 1 hour, 1.5 ml of glacial aceticacid was added and the mixture was returned to room temperature. Afteradding 40 ml of water, the mixture was extracted with diethyl ether. Theorganic layer was sequentially washed with 1 N hydrochloric acid, water,saturated aqueous sodium hydrogencarbonate solution and brine, driedover anhydrous magnesium sulfate and the solvent was evaporated. Thecrude product was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:9), to give 1.35 g of the titlecompound as a pale yellow viscous oil.

¹H-NMR (400 MHz, DMSO-D₆) δ 0.40 (9H, s), 5.97 (1H, d, J=4.0 Hz), 6.35(1H, d, J=4.0 Hz), 7.08 (1H, td, J=8.0, 2.8 Hz), 7.15 (1H, d, J=8.0 Hz),7.17 (1H, dd, J=8.0, 2.8 Hz), 7.37 (1H, td, J=8.0, 6.0 Hz), 7.72 (1H, d,J=8.0 Hz), 7.76 (1H, t, J=8.0 Hz).

Production Example I-3-c 3-(3-Fluorophenyl)-1H-6-indazolecarbonitrile

To a solution of 1.35 g of3-fluoro-4-[(3-fluorophenyl)(hydroxy)methyl]-2-(1,1,1-trimethylsilyl)benzonitrilein 30 ml methylene chloride was added 4.5 g of activated manganesedioxide, the mixture was stirred at room temperature for five days, andthen the manganese dioxide was filtered off through Celite. Afterremoving the solvent by distillation, the residue was dissolved in 5 mlof tetrahydrofuran and 5 ml of methanol, 1.0 ml of hydrazine monohydratewas added and the mixture was stirred at room temperature for 1 day. Thereaction mixture was added with water and extracted with ethyl acetate.The organic layer was sequentially washed with water and brine, driedover anhydrous magnesium sulfate and the solvent was removed. Then, theresulting crystals were suspended in diisopropyl ether, to give 62 mg ofthe title compound as pale yellow crystals. After concentrating themother liquor, the residue was purified and separated by silica gelcolumn chromatography (ethyl acetate:toluene=1:9), to give 30 mg of thetitle compound as yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.29 (1H, td, J=8.0, 2.8 Hz), 7.54 (1H, dd,J=8.4, 1.2 Hz), 7.59 (1H, td, J=8.0, 6.4 Hz), 7.77 (1H, dd, J=10.4, 2.8Hz), 7.86 (1H, d, J=8.0 Hz), 8.26 (1H, s), 8.31 (1H, d, J=8.4 Hz), 13.96(1H, s).

Production Example I-3-d 3-(3-Fluorophenyl)-1H-6-indazolecarboxylic acid

To 92 mg of 3-(3-fluorophenyl)-1H-6-indazolecarbonitrile weresequentially added 1 ml of glacial acetic acid, 0.5 ml of water and 0.4ml of concentrated sulfuric acid, and the mixture was stirred at 110° C.for 6 hours. After standing to cool, 35 ml of ethyl acetate was added tothe reaction mixture. The mixture was sequentially washed with water andbrine, dried over anhydrous magnesium sulfate and the solvent wasevaporated, to give 94 mg of the title compound as bright yellowcrystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.27 (1H, td, J=8.4, 2.4 Hz), 7.59 (1H, td,J=8.0, 6.4 Hz), 7.74-7.81 (2H, m), 7.88 (1H, d, J=8.0 Hz), 8.19 (1H, s),8.20 (1H, d, J=9.6 Hz), 8.65 (1H, s), 13.14 (1H, s), 13.71 (1H, s).

Production Example I-4-a[5-(Dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanol

A total of 21.6 g of 3-bromo-4-fluorobenzaldehyde was dissolved in amixture of 50 ml of methyl orthoformate and 50 ml of methanol, and 0.2 gof p-toluenesulfonic acid monohydrate was added, followed by stirring atroom temperature for 1 hour. To the reaction mixture was added aqueoussodium hydrogencarbonate solution, and the mixture was extracted withethyl acetate. The organic layer was washed with water, dried overanhydrous magnesium sulfate and the solvent was evaporated, to give 24.3g of 3-bromo-4-fluorobenzaldehyde dimethylacetal as a colorless oil. Theproduct was dissolved in 150 ml of dry tetrahydrofuran. After cooling to−78° C. in an atmosphere of nitrogen gas, 59 ml of a 2.5 M solution ofn-butyllithium in hexane was added. After stirring for 30 minutes, 12.7ml of 3-fluorobenzaldehyde was added and the mixture was heated to roomtemperature. To the reaction mixture was added aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate for twotimes. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and the solvent was evaporated. The residue waspurified and separated by silica gel column chromatography (ethylacetate:hexane=1:15), to give 24.3 g of the title compound as a paleyellow oil.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.20 (3H, s), 3.31 (3H, s), 5.36 (1H, s),5.93 (1H, d, J=4.4 Hz), 6.19 (1H, d, J=4.4 Hz), 7.00-7.07 (1H, m),7.07-7.15 (3H, m), 7.25-7.30 (1H, m), 7.30-7.38 (1H, m), 7.56 (1H, dd,J=2.8, 7.4 Hz).

Production Example I-4-b[5-(Dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanone

In a mixture of 80 ml of dichloromethane and 80 ml of dimethylsulfoxidewere dissolved 24.3 g of[5-(dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanol and 27.6 mlof triethylamine, and a suspension of 26.3 g of sulfur trioxide-pyridinecomplex in 30 ml dimethyl sulfoxide was added, followed by stirring atroom temperature for 1 hour. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate for two times. Theorganic layer was washed with water, dried over anhydrous magnesiumsulfate and the solvent was evaporated. The residue was purified andseparated by silica gel column chromatography (ethylacetate:hexane=1:15), to give 18.7 g of the title compound as acolorless oil.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.25 (6H, s), 5.45 (1H, s), 7.40 (1H, dd,J=8.8, 10.5 Hz), 7.51-7.63 (5H, m), 7.63-7.69 (1H, m).

Production Example I-4-c

The title compound was also synthetically prepared by another procedureas mentioned below. A total of 2.0 g of[5-(dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanol wasdissolved in 20 ml of dichloromethane, and the solution was treated with5 g of manganese dioxide with stirring at room temperature for one day.The reaction mixture was filtrated using a Celite, the solvent wasremoved by distillation under reduced pressure, to give 2.0 g of thetitle compound.

Production Example I-4-d Methyl 4-fluoro-3-(3-fluorobenzoyl)benzoate

A total of 18.7 g of[5-(dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanone wasdissolved in 100 ml of tetrahydrofuran, and 5 ml of 5 N hydrochloricacid was added, followed by stirring at room temperature for 1 hour. Tothe reaction mixture was added saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate for two times. The organic layer was washed with water, driedover anhydrous magnesium sulfate and the solvent was evaporated, to give15.8 g of 4-fluoro-3-(3-fluorobenzoyl)benzaldehyde as a colorless oil. Atotal of 13.8 g of this compound was dissolved in 50 ml of dimethylsulfoxide, and a solution of 15.2 g of sodium chlorite in 50 ml waterwas added dropwise over 1 hour under ice-cooling. To the reactionmixture was added diluted hydrochloric acid, and the mixture wasextracted with ethyl acetate for two times. The organic layer was washedwith water, dried over anhydrous magnesium sulfate and the solvent wasevaporated. The residue was filtered using diisopropyl ether, to give12.9 g of 4-fluoro-3-(3-fluorobenzoyl)benzoic acid as a colorless solid.A total of 11.1 g of this compound was dissolved in 50 ml ofN,N-dimethylformamide, and 5.8 g of potassium carbonate and 2.9 ml ofmethyl iodide were added, followed by stirring at room temperature for12 hours. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate for two times. The organic layer was washedwith water, dried over anhydrous magnesium sulfate and the solvent wasevaporated. The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:15), to give 11.5 g of the titlecompound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.93 (3H, s), 7.25 (1H, t, J=9.2 Hz), 7.32(1H, ddt, J=1.2, 2.7, 8.0 Hz), 7.46 (1H, dt, J=5.3, 8.0 Hz), 7.50-7.59(2H, m), 8.21-7.26 (2H, m).

Production Example I-4-e Methyl3-(3-fluorophenyl)-1H-5-indazolecarboxylate

A total of 11.5 g of methyl 4-fluoro-3-(3-fluorobenzoyl)benzoate wasdissolved in 40 ml of ethanol, and the reaction mixture was treated with2.4 ml of hydrazine monohydrate with stirring at room temperature for 12hours. The reaction mixture was treated with 2 N hydrochloric acid to beacidic and was extracted with two portions of ethyl acetate. The organiclayer was washed with water, dried over anhydrous magnesium sulfate andthe solvent was evaporated. The residue was recrystallized fromhexane-diisopropyl ether, to give 7.0 g of title compound as colorlesscrystals.

¹H-NMR (400 MHz, CDCl₃) δ 3.96 (3H, s), 7.16 (1H, t, J=8.3 Hz),7.48-7.55 (2H, m), 7.70 (1H, d, J=10.0 Hz), 7.79 (1H, d, J=8.8 Hz), 8.12(1H, d, J=8.8 Hz), 8.77 (1H, s).

Production Example I-4-f 3-(3-Fluorophenyl)-1H-5-indazolecarboxylic acid

A total of 2.1 g of the title compound as a colorless powder wasobtained by the procedure of Production Example I-5-b, except from 2.7 gof methyl 3-(3-fluorophenyl)-1H-5-indazolecarboxylate.

The ¹H-NMR spectrum thereof agrees with that of the compound accordingto Production Example I-1-c.

Production Example I-5-a Methyl3-(2-fluorophenyl)-1H-5-indazolecarboxylate

A total of 1.9 g of the title compound was obtained as a colorlesspowder by the procedures of Production Examples I-4-a, I-4-c, I-4-d, andI-4-e, except from 3.7 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a and 1.73 ml of 2-fluorobenzaldehydeas starting materials.

¹H-NMR (400 MHz, CDCl₃) δ 3.95 (3H, s), 7.26-7.32 (1H, m), 7.32 (1H, dt,J=1.7, 7.4 Hz), 7.44-7.51 (1H, m), 7.53 (1H, d, J=8.7 Hz), 7.82 (1H, dt,J=1.7, 7.4 Hz), 8.13 (1H, dd, J=1.6, 8.7 Hz), 8.64 (1H, bs).

Production Example I-5-b 3-(2-Fluorophenyl)-1H-5-indazolecarboxylic acid

A total of 1.6 g of methyl 3-(2-fluorophenyl)-1H-5-indazolecarboxylatewas dissolved in 15 ml of a 1:1 solvent mixture of methanol andtetrahydrofuran, 2 ml of 5 N aqueous sodium hydroxide solution wasadded, followed by heating at 70° C. for 6 hours. After cooling to roomtemperature, the reaction mixture was added with diluted hydrochloricacid and was extracted with ethyl acetate for two times. The organiclayer was washed with water, dried over anhydrous magnesium sulfate andthe solvent was evaporated, to give 1.5 g of the title compound as acolorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.38 (1H, dt, J=1.2, 7.5 Hz), 7.43 (1H, ddd,J=1.2, 8.3, 10.9 Hz), 7.50-7.57 (1H, m), 7.66 (1H, d, J=8.7 Hz), 7.80(1H, dd, J=1.9, 7.5 Hz), 7.95 (1H, dd, J=1.2, 8.7 Hz), 8.39 (1H, bs),13.71 (1H, s).

Production Example I-6-a Methyl 3-(2-pyridyl)-1H-5-indazolecarboxylate

A total of 1.0 g of the title compound was obtained as a colorlesspowder by the procedures of Production Examples I-4-a, I-4-c, I-4-d, andI-4-e, except from 3.7 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a and 1.6 ml of2-pyridinecarboxaldehyde as starting materials.

¹H-NMR (400 MHz, CDCl₃) δ 3.88 (3H, s), 7.31 (1H, ddd, J=1.8, 5.2, 7.8Hz), 7.54 (1H, d, J=8.6 Hz), 7.82 (1H, dt, J=1.8, 7.8 Hz), 8.13 (1H, dd,J=1.8, 8.6 Hz), 8.19 (1H, d, J=7.8 Hz), 8.81 (1H, dd, J=1.8, 5.2 Hz),9.42 (1H, d, J=1.8 Hz).

Production Example I-6-b 3-(2-Pyridyl)-1H-5-indazolecarboxylic acid

A total of 0.8 g of the title compound was obtained as a pale yellowpowder by the procedure of Production Example I-5-b, except from 1.0 gof methyl 3-(2-pyridyl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, CDCl₃) δ 7.39 (1H, ddd, J=1.8, 4.6, 7.5 Hz), 7.64 (1H,d, J=8.5 Hz), 7.91 (1H, dt, J=1.8, 7.5 Hz), 7.95 (1H, dd, J=1.8, 8.5Hz), 8.18 (1H, d, J=8.5 Hz), 8.77 (1H, dd, J=1.8, 4.6 Hz), 9.25 (1H, s),13.63 (1H, bs).

Production Example I-7-a Methyl 3-(3-pyridyl)-1H-5-indazolecarboxylate

A total of 0.88 g of the title compound was obtained as a colorlesspowder by the procedures of Production Examples I-4-a, I-4-c, I-4-d, andI-4-e, except from 6.5 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a and 2.7 ml of3-pyridinecarboxaldehyde as starting materials.

¹H-NMR (400 MHz, CDCl₃) δ 3.96 (3H, s), 7.49 (1H, dd, J=5.1, 7.6 Hz),7.57 (1H, d, J=9.1 Hz), 8.15 (1H, dd, J=1.0, 9.1 Hz), 8.30 (1H, dt,J=2.0, 7.6 Hz), 8.71 (1H, dd, J=2.0, 5.1 Hz), 8.78 (1H, d, J=1.0 Hz),9.18 (1H, d, J=2.0 Hz).

Production Example I-7-b 3-(3-Pyridyl)-1H-5-indazolecarboxylic acid

A total of 0.66 g of the title compound was obtained as a pale yellowpowder by the procedure of Production Example I-5-b, except from 0.88 gof methyl 3-(3-pyridyl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.58 (1H, dd, J=5.2, 8.0 Hz), 7.68 (1H, d,J=8.8 Hz), 7.98 (1H, dd, J=1.5, 8.8 Hz), 8.34 (1H, dt, J=1.9, 8.0 Hz),8.62 (1H, s), 8.64 (1H, dd, J=1.9, 5.2 Hz), 9.15 (1H, d, J=1.9 Hz),12.80-12.95 (1H, bs), 13.73 (1H, s).

Production Example I-8-a Methyl3-(2-methoxyphenyl)-1H-5-indazolecarboxylate

A total of 2.2 g of the title compound was obtained as a colorless oilby the procedures of Production Examples I-4-a, I-4-c, I-4-d, and I-4-e,except from 3.7 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a and 2.0 ml of o-anisaldehyde asstarting materials.

¹H-NMR (400 MHz, CDCl₃) δ 3.89 (3H, s), 3.93 (3H, s), 7.11 (1H, d, J=8.3Hz), 7.13 (1H, t, J=7.5 Hz), 7.47 (1H, dt, J=1.7, 8.7 Hz), 7.50 (1H, d,J=8.3 Hz), 7.68 (1H, dd, J=1.7, 7.5 Hz), 8.07 (1H, dd, J=1.7, 8.7 Hz),8.58 (1H, s).

Production Example I-8-b 3-(2-Methoxyphenyl)-1H-5-indazolecarboxylicacid

A total of 2.1 g of the title compound was obtained as a colorlesspowder by the procedure of Production Example I-5-b, except from 2.2 gof methyl 3-(2-methoxyphenyl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.79 (3H, s), 7.07 (1H, dt, J=1.2, 7.1 Hz),7.20 (1H, d, J=7.4 Hz), 7.46 (1H, ddd, J=1.9, 7.1, 9.1 Hz), 7.53 (1H, d,J=1.9, 7.4 Hz), 7.58 (1H, dd, J=1.2, 9.1 Hz), 7.90 (1H, dd, J=1.6, 9.1Hz), 8.29 (1H, s), 13.35-13.50 (1H, bs).

Production Example I-9-a Methyl 3-(2-quinolyl)-1H-5-indazolecarboxylate

A total of 1.3 g of the title compound was obtained as a colorlesspowder by the procedures of Production Examples I-4-a, I-4-c, I-4-d, andI-4-e, except from 3.7 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a and 2.4 g of2-quinolinecarboxaldehyde as starting materials.

¹H-NMR (400 MHz, CDCl₃) δ 4.03 (3H, s), 7.57 (1H, d, J=8.2 Hz), 7.59(1H, dd, J=1.8, 8.2 Hz), 7.78 (1H, dt, J=1.8, 8.2 Hz), 7.86 (1H, d,J=8.2 Hz), 8.17 (1H, dd, J=1.8, 8.2 Hz), 8.27 (1H, d, J=8.2 Hz), 8.33(1H, d, J=8.2 Hz), 8.35 (1H, d, J=8.2 Hz), 9.62 (1H, s).

Production Example I-9-b 3-(2-Quinolyl)-1H-5-indazolecarboxylic acid

A total of 1.1 g of the title compound was obtained as a pale yellowpowder by the procedure of Production Example I-5-b, except from 1.3 gof methyl 3-(2-quinolyl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.62 (1H, ddd, J=0.9, 6.9, 8.0 Hz), 7.69(1H, dd, J=0.9, 8.7 Hz), 7.82 (1H, ddd, J=1.5, 6.9, 8.0 Hz), 8.00 (1H,dd, J=1.8, 8.7 Hz), 8.01 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=8.0 Hz), 8.35(1H, d, J=8.0 Hz), 8.46 (1H, d, J=8.7 Hz), 9.53 (1H, s), 13.80 (1H, s).

Production Example I-10-a Methyl 3-(3-quinolyl)-1H-5-indazolecarboxylate

A total of 2.1 g of the title compound was obtained as a pale yellowpowder by the procedures of Production Examples I-4-a, I-4-c, I-4-d, andI-4-e, except from 4.98 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a and 3.14 g of3-quinolinecarboxaldehyde as starting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.90 (3H, s), 7.68 (1H, t, J=7.6 Hz), 7.74(1H, d, J=8.7 Hz), 7.81 (1H, t, J=7.6 Hz), 8.02 (1H, dd, J=1.6, 8.7 Hz),8.08 (1H, d, J=7.6 Hz), 8.22 (1H, d, J=7.6 Hz), 8.80 (1H, s), 8.94 (1H,d, J=2.3 Hz), 9.50 (1H, d, J=2.3 Hz).

Production Example I-10-b 3-(3-Quinolyl)-1H-5-indazolecarboxylic acid

A total of 1.9 g of the title compound was obtained as a pale yellowpowder by the procedure of Production Example I-5-b, except from 2.1 gof methyl 3-(3-quinolyl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.65 (1H, t, J=7.6 Hz), 7.68 (1H, d, J=8.7Hz), 7.80 (1H, t, J=7.6 Hz), 8.02 (1H, dd, J=1.4, 8.7 Hz), 8.22 (1H, d,J=7.6 Hz), 8.22 (1H, d, J=7.6 Hz), 8.77 (1H, s), 8.93 (1H, d, J=2.3 Hz),9.51 (1H, d, J=2.3 Hz), 13.75-13.85 (1H, bs).

Production Example I-11-a Methyl 3-(4-quinolyl)-1H-5-indazolecarboxylate

A total of 2.00 g of the title compound was obtained as a colorlesspowder by the procedures of Production Examples I-4-a, I-4-c, I-4-d, andI-4-e, except from 4.98 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a and 3.14 g of4-quinolinecarboxaldehyde as starting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.83 (3H, s), 7.64 (1H, t, J=7.6 Hz), 7.80(1H, d, J=9.2 Hz), 7.83 (1H, t, J=7.6 Hz), 7.83 (1H, d, J=4.3 Hz), 8.03(1H, dd, J=1.2, 9.2 Hz), 8.14 (1H, d, J=7.6 Hz), 8.38 (1H, d, J=1.2 Hz),8.39 (1H, d, J=7.6 Hz), 9.07 (1H, d, J=4.3 Hz).

Production Example I-11-b 3-(4-Quinolyl)-1H-5-indazolecarboxylic acid

A total of 1.8 g of the title compound was obtained as a pale yellowpowder by the procedure of Production Example I-5-b, except from 2.0 gof methyl 3-(4-quinolyl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.65 (1H, t, J=7.5 Hz), 7.77 (1H, d, J=8.7Hz), 7.84 (1H, t, J=7.5 Hz), 7.85 (1H, d, J=4.4, Hz), 8.02 (1H, dd,J=1.4, 8.7 Hz), 8.14 (1H, d, J=7.6 Hz), 8.37 (1H, s), 8.43 (1H, d, J=7.6Hz), 9.08 (1H, d, J=4.4 Hz), 14.00 (1H, s).

Production Example I-12-a Methyl 3-(2-naphthyl)-1H-5-indazolecarboxylate

A total of 5.70 g of the title compound was obtained as a colorlesspowder by the procedures of Production Examples I-4-a, I-4-c, I-4-d, andI-4-e, except from 7.50 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a and 5.20 g of 2-naphthylaldehyde asstarting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.88 (3H, s), 7.53-7.60 (2H, m), 7.71 (1H,dd, J=0.9, 8.8 Hz), 7.96-7.99 (1H, m), 8.00 (1H, dd, J=1.3, 8.8 Hz),8.08 (1H, d, J=8.8 Hz), 8.10-8.13 (m, 1H), 8.12 (1H, dd, J=1.8, 8.8 Hz),8.51 (bs, 1H), 8.78 (1H, dd, J=0.9, 1.3 Hz).

Production Example I-12-b 3-(2-Naphthyl)-1H-5-indazolecarboxylic acid

A total of 0.9 g of the title compound was obtained as white crystals bythe procedure of Production Example I-5-b, except from 1.0 g of methyl3-(2-naphthyl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.34-7.62 (2H, m), 7.70 (1H, d, J=8.8 Hz),7.96-8.04 (2H, m), 8.10 (1H, d, J=8.8 Hz), 8.12-8.18 (2H, m), 8.55 (1H,s), 8.79 (1H, s), 12.92 (1H, s), 13.66 (1H, s).

Production Example I-13-a 5-(Dimethoxymethyl)-2-fluorobenzaldehyde

A total of 2.49 g of 3-bromo-4-fluorobenzaldehyde dimethylacetalproduced in Production Example I-4-a was dissolved in 20 ml of drytetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogengas, 8.5 ml of a 1.56 M solution of n-butyllithium in hexane was added.After stirring for 30 minutes, 1.0 ml of N,N-dimethylformamide was addedand the mixture was heated to room temperature. To the reaction mixturewas added aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate for two times. The organic layer was washedwith water, dried over anhydrous magnesium sulfate and the solvent wasevaporated. The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:12.5), to give 1.35 g of thetitle compound as a colorless oil.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.24 (6H, s), 5.45 (1H, s), 7.42 (1H, dd,J=9.0, 10.0 Hz), 7.68-7.75 (1H, m), 7.82 (1H, dd, J=2.0, 7.0 Hz), 10.21(1H, s).

Production Example I-13-b1,3-Benzothiazol-2-yl[5-(dimethoxymethyl)-2-fluorophenyl]methanol

A total of 1.08 g of benzothiazole was dissolved in 15 ml of drytetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogengas, 6.4 ml of 1.56 M solution of n-butyllithium in hexane was added.After stirring for 5 minutes, 8 ml of a solution of 1.35 g of5-(dimethoxymethyl)-2-fluorobenzaldehyde in dry tetrahydrofuran wasadded, followed by stirring for 10 minutes. To the reaction mixture wasadded aqueous ammonium chloride solution, and the mixture was extractedwith ethyl acetate for two times. The organic layer was washed withwater, dried over anhydrous magnesium sulfate and the solvent wasevaporated. The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=3:7), to give 1.8 g of the titlecompound as a yellow oil.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.20 (6H, s), 5.35 (1H, s), 6.25 (1H, s),7.11-7.16 (1H, bs), 7.21 (1H, dd, J=8.2, 9.7 Hz), 7.32-7.37 (1H, m),7.39 (1H, t, J=7.7 Hz), 7.45 (1H, t, J=7.7 Hz), 7.55 (1H, d, J=2.6, 6.7Hz), 7.88 (1H, d, J=7.7 Hz), 8.08 (1H, d, J=7.7 Hz).

Production Example I-13-c Methyl3-(1,3-benzothiazol-2-yl)-1H-5-indazolecarboxylate

A total of 1.05 g of the title compound was obtained as a colorlesspowder by the procedures of Production Examples I-4-c, I-4-d, and I-4-e,except from 1.8 g of1,3-benzothiazol-2-yl[5-(dimethoxymethyl)-2-fluorophenyl]methanol as astarting material.

¹H-NMR (400 MHz, CDCl₃) δ 4.02 (3H, s), 7.45 (1H, ddd, J=1.1, 7.2, 8.4Hz), 7.55 (1H, ddd, J=1.1, 7.2, 8.4 Hz), 7.59 (1H, dd, J=0.9, 8.9 Hz),7.97 (1H, ddd, J=0.7, 1.1, 8.1 Hz), 8.20 (1H, dd, J=1.4, 8.9 Hz), 8.23(1H, ddd, J=0.7, 1.1, 8.1 Hz), 9.41 (1H, dd, J=0.9, 1.4 Hz), 10.36-10.48(1H, bs).

Production Example I-13-d3-(1,3-Benzothiazol-2-yl)-1H-5-indazolecarboxylic acid

A total of 0.95 g of the title compound was obtained as a colorlesspowder by the procedure of Production Example I-5-b, except from 1.2 gof methyl 3-(1,3-benzothiazol-2-yl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.39 (1H, t, J=7.2 Hz), 7.57 (1H, t, J=7.2Hz), 7.75 (1H, dd, J=0.8, 8.6 Hz), 8.04 (1H, dd, J=1.8, 8.6 Hz), 8.16(1H, d, J=7.2 Hz), 8.19 (1H, d, J=7.2 Hz), 9.14 (1H, dd, J=0.8, 1.8 Hz),12.80-13.20 (1H, bs), 14.07 (1H, s).

Production Example I-14-a 3-Bromo-1H-5-indazolecarbonitrile

To a solution of 300 mg of a compound 1H-5-indazolecarbonitrile(synthesized from 4-fluorobenzonitrile according to the proceduresdescribed in literature, Tetrahedron Lett., 33, 7499 (1992) andSynthetic commun., 27, 1199 (1997)) in 3 ml dimethylformamide was added392 mg of N-bromosuccinimide at room temperature, and the mixture wasstirred at the same temperature for one day. After removing the solventby distillation, the residue was added with 25 ml of ethyl acetate. Themixture was sequentially washed with half-saturated aqueous sodiumhydrogencarbonate solution, water and brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated, to give 440 mg of thetitle compound as pale red crystals.

¹H-NMR (400 MHz, CDCl₃) δ 7.59 (1H, dd, J=8.4, 0.8 Hz), 7.67 (1H, dd,J=8.4, 1.6 Hz), 8.07 (1H, dd, J=1.6, 0.8 Hz).

Production Example I-14-b tert-Butyl3-bromo-5-cyano-1H-1-indazolecarboxylate

To a solution of 6.25 g of 3-bromo-1H-5-indazolecarbonitrile in 100 mltetrahydrofuran at room temperature were added 6.76 g of di-tert-butyldicarbonate and 516 mg of 4-(dimethylamino)pyridine, and the mixture wasstirred at the same temperature overnight. After removing the solvent bydistillation, the residue was added with 220 ml of ethyl acetate. Themixture was sequentially washed with diluted hydrochloric acid, water,saturated aqueous sodium hydrogencarbonate solution and brine, driedover anhydrous magnesium sulfate and the solvent was evaporated, to give8.69 g of the title compound as pale red crystals.

¹H-NMR (400 MHz, CDCl₃) δ 1.73 (9H, s), 7.80 (1H, dd, J=8.8, 1.6 Hz),8.03 (1H, d, J=1.6 Hz), 8.30 (1H, d, J=8.8 Hz).

Production Example I-14-c 3-(4-Fluorophenyl)-1H-5-indazolecarbonitrile

To a solution of 2.0 g of tert-butyl3-bromo-5-cyano-1H-1-indazolecarboxylate in 30 ml tetrahydrofuran wereadded 70 mg of palladium(II) acetate, 218 mg of2-(dicyclohexylphosphino)biphenyl, 1.19 g of potassium fluoride and 1.30g of 4-fluorophenylboronic acid, and the mixture was stirred at 50° C.for one day. After removing the solvent by distillation, the residue wasdiluted with 40 ml of ethyl acetate. The mixture was sequentially washedwith water and brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated. The residue was dissolved in 25 ml of methylenechloride, and 5 ml of trifluoroacetic acid was added, followed bystirring at room temperature for 1 hour. After removing the solvent bydistillation, the residue was diluted with 40 ml of ethyl acetate. Themixture was sequentially washed with saturated aqueous sodiumhydrogencarbonate solution and brine, dried over anhydrous magnesiumsulfate and the solvent was evaporated. The crude product was purifiedand separated by silica gel column chromatography (ethylacetate:toluene=1:19 to 1:9), to give 1.09 g of the title compound asbright yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.36 (2H, t, J=8.8 Hz), 7.74 (1H, dd, J=8.8,1.2 Hz), 7.76 (1H, dd, J=8.8, 1.2 Hz), 8.10 (2H, dd, J=8.8, 5.6 Hz),8.71 (1H, s), 13.78 (1H, s).

Production Example I-14-d 3-(4-Fluorophenyl)-1H-5-indazolecarboxylicacid

To 1.0 g of 3-(4-fluorophenyl)-1H-5-indazolecarbonitrile were added 5 mlof water, 4 ml of concentrated sulfuric acid and 4 ml of glacial aceticacid, and the mixture was heated under reflux for 3 hours. Afterstanding to cool, 25 ml of ice-cooled water was added. The resultingcrystals were collected by filtration. The collected crystals weredissolved in 250 ml of ethyl acetate, sequentially washed with water andbrine, and dried over anhydrous magnesium sulfate. After filtrating theorganic layer through a silica gel pat, the solvent was evaporated, togive 968 mg of the title compound as bright yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.41 (2H, t, J=8.8 Hz), 7.66 (1H, d, J=8.8Hz), 7.95-8.09 (3H, m), 8.63 (1H, s), 12.91 (1H, s), 13.58 (1H, s).

Production Example I-15-a 3-(3-Chlorophenyl)-1H-5-indazolecarbonitrile

A total of 137 mg of the title compound was obtained as white crystalsby the procedure of Production Example I-14-c, except from 2.0 g oftert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced inProduction Example I-14-b and 1.46 g of 3-chlorophenylboronic acid.

¹H-NMR (400 MHz, CDCl₃) δ 7.46 (1H, dt, J=8.0, 1.6 Hz), 7.51 (1H, d,J=8.4 Hz), 7.64 (1H, t, J=8.0 Hz), 7.67 (1H, dd, J=8.4, 1.2 Hz), 7.81(1H, dt, J=8.0, 1.6 Hz), 7.93 (1H, t, J=1.6 Hz), 8.40 (1H, d, J=1.2 Hz).

Production Example I-15-b 3-(3-Chlorophenyl)-1H-5-indazolecarboxylicacid

A total of 115 mg of the title compound was obtained as beige crystalsby the procedure of Production Example I-14-d, except using 135 mg of3-(3-chlorophenyl)-1H-5-indazolecarbonitrile.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.53 (1H, dd, J=8.0, 1.6 Hz), 7.62 (1H, td,J=8.0, 1.6 Hz), 7.69 (1H, d, J=8.0 Hz), 7.93-8.05 (3H, m), 8.63 (1H, s),12.90 (1H, s), 13.71 (1H, s).

Production Example I-16-a3-[3-(Trifluoromethyl)phenyl]-1H-5-indazolecarbonitrile

A total of 58 mg of the title compound was obtained as white crystals bythe procedure of Production Example I-14-c, except using 500 mg oftert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced inProduction Example I-14-b and 442 mg of 3-trifluoromethylphenylboronicacid.

¹H-NMR (400 MHz, CDCl₃). δ 7.63-7.76 (4H, m), 8.11 (1H, d, J=7.6 Hz),8.21 (1H, s), 8.40 (1H, s).

Production Example I-16-b3-[3-(Trifluoromethyl)phenyl]-1H-5-indazolecarboxylic acid

A total of 54 mg of the title compound was obtained as beige crystals bythe procedure of Production Example I-14-d, except using 57 mg of3-[3-(trifluoromethyl)phenyl]-1H-5-indazolecarbonitrile.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.71 (1H, d, J=8.4 Hz), 7.83 (2H, m), 8.01(1H, d, J=8.8 Hz), 8.24 (1H, s), 8.32 (1H, m), 8.66 (1H, s), 12.96 (1H,s), 13.77 (1H, s).

Production Example I-17-a3-Benzo[b]thiophen-2-yl-1H-5-indazolecarbonitrile

To a solution of 600 mg of tert-butyl3-bromo-5-cyano-1H-1-indazolecarboxylate produced in Production ExampleI-14-b in 9 ml tetrahydrofuran were added 21 mg of palladium(II)acetate, 57 mg of 2-(di-tert-butylphosphino)biphenyl, 357 mg ofpotassium fluoride and 498 mg of 2-benzo[b]thiopheneboronic acid, andthe mixture was stirred at 50° C. for 1 hour. After removing the solventby distillation, the residue was dissolved in 2 ml of methylenechloride. 4 ml of trifluoroacetic acid was added and the mixture wasstirred at room temperature for one day. After removing the solvent bydistillation, the residue was diluted with 50 ml of ethyl acetate. Themixture was sequentially washed with saturated aqueous sodiumhydrogencarbonate solution and brine, dried over anhydrous magnesiumsulfate and the solvent was evaporated. The crude product was purifiedand separated by silica gel column chromatography (ethylacetate:toluene=1:19), to give 294 mg of the title compound as brightyellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.41 (2H, t, J=7.8 Hz), 7.44 (2H, t, J=7.8Hz), 7.80 (2H, s), 7.91 (1H, d, J=8.0 Hz), 8.01 (1H, d, J=8.0 Hz), 8.41(1H, s), 8.99 (1H, s), 13.88 (1H, s).

Production Example I-17-b3-Benzo[b]thiophen-2-yl-1H-5-indazolecarboxylic acid

To 288 mg of 3-benzo[b]thiophen-2-yl-1H-5-indazolecarbonitrile wereadded 3 ml of glacial acetic acid, 1 ml of water and 0.8 ml ofconcentrated sulfuric acid, and the mixture was stirred at 110° C. for 4hours. After standing to cool, the mixture was added with 120 ml ofethyl acetate, sequentially washed with water and brine, dried overanhydrous magnesium sulfate. After filtering the organic layer through asilica gel pat, the solvent was evaporated, to give 307 mg of the titlecompound as ocher yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.36-7.48 (2H, m), 7.71 (1H, d, J=8.8 Hz),7.99-8.07 (3H, m), 8.17 (1H, s), 8.83 (1H, s), 13.72 (1H, s).

Production Example I-18-a 3-(3-Methoxyphenyl)-1H-5-indazolecarbonitrile

A total of 66 mg of the title compound was obtained as bright yellowcrystals by the procedure of Production Example I-17-a, except from 200mg of tert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced inProduction Example I-14-b and 142 mg of 3-methoxyphenylboronic acid.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.87 (3H, s), 7.03 (1H, dd, J=8.0, 2.4 Hz),7.46 (1H, t, J=8.0 Hz), 7.51 (1H, s), 7.62 (1H, d, J=8.0 Hz), 7.73 (1H,d, J=8.8 Hz), 7.77 (1H, d, J=8.8 Hz), 8.67 (1H, s), 13.76 (1H, s).

Production Example I-18-b 3-(3-Methoxyphenyl)-1H-5-indazolecarboxylicacid

A total of 14 mg of the title compound was obtained as orange crystalsby the procedure of Production Example I-17-b, except from 65 mg of3-(3-methoxyphenyl)-1H-5-indazolecarbonitrile.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.86 (3H, s), 7.04 (1H, dd, J=8.4, 2.4 Hz),7.50 (1H, t, J=8.0 Hz), 7.54 (1H, s), 7.61 (1H, d, J=8.0 Hz), 7.66 (1H,d, J=8.0 Hz), 7.93 (1H, d, J=8.4 Hz), 8.60 (1H, s), 12.85 (1H, s), 13.44(1H, s).

Production Example I-19-a3-Benzo[b]thiophen-3-yl-1H-5-indazolecarbonitrile

A total of 303 mg of the title compound was obtained as light browncrystals by the procedure of Production Example I-17-a, except from 500mg of tert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced inProduction Example I-14-b and 415 mg of 3-benzo[b]thiopheneboronic acid.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.45-7.55 (2H, m), 7.77 (1H, d, J=8.8 Hz),7.82 (1H, d, J=8.8 Hz), 8.11 (1H, d, J=7.2 Hz), 8.60 (1H, s), 8.70 (1H,d, J=7.2 Hz), 8.77 (1H, s), 13.85 (1H, s).

Production Example I-19-b3-Benzo[b]thiophen-3-yl-1H-5-indazolecarboxylic acid

A total of 301 mg of the title compound was obtained as red crystals bythe procedure of Production Example I-17-b, except from 300 mg of3-benzo[b]thiophen-3-yl-1H-5-indazolecarbonitile.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.45-7.55 (2H, m), 7.71 (1H, d, J=8.8 Hz),8.01 (1H, d, J=8.8 Hz), 8.11 (1H, d, J=7.2 Hz), 8.40 (1H, s), 8.57 (1H,d, J=7.2 Hz), 8.66 (1H, s), 12.89 (1H, s), 13.65 (1H, s).

Production Example I-20-a3-(5-Acetyl-2-thienyl)-1H-5-indazolecarbonitrile

A total of 94 mg of the title compound was obtained as green crystals bythe procedure of Production Example I-17-a, except from 500 mg oftert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced inProduction Example I-14-b and 528 mg of 5-acetyl-2-thiopheneboronicacid.

¹H-NMR (400 MHz, DMSO-D₆) δ 2.59 (3H, s), 7.78 (1H, d, J=8.8 Hz), 7.81(1H, d, J=8.8 Hz), 8.03 (1H, d, J=4.0 Hz), 8.08 (1H, d, J=4.0 Hz), 8.87(1H, s), 13.98 (1H, s).

Production Example I-20-b 3-(5-Acetyl-2-thienyl)-1H-5-indazolecarboxylicacid

A total of 85 mg of the title compound was obtained as ocher yellowcrystals by the procedure of Production Example I-17-b, except from 94mg of 3-(5-acetyl-2-thienyl)-1H-5-indazolecarbonitrile.

¹H-NMR (400 MHz, DMSO-D₆) δ 2.59 (3H, s), 7.70 (1H, d, J=8.8 Hz), 7.87(1H, d, J=3.6 Hz), 8.01 (1H, d, J=8.8 Hz), 8.03 (1H, d, J=3.6 Hz), 8.69(1H, s), 13.00 (1H, s), 13.82 (1H, s).

Production Example I-21-a 1H-5-Indazolecarboxylic acid

To 867 mg of 1H-5-indazolecarbonitrile used in Production Example I-14-awere added 8 ml of glacial acetic acid, 2.5 ml of water and 2 ml ofconcentrated sulfuric acid, and the mixture was stirred at 110° C. for10 hours. After standing to cool, the mixture was added with 50 ml ofwater, and the resulting crystals were collected by filtration and driedin vacuo, to give 911 mg of the title compound as white crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.59 (1H, dd, J=0.8, 8.8 Hz), 7.91 (1H, dd,J=0.8, 8.8 Hz), 8.24 (1H, s), 8.45 (1H, s), 13.36 (1H, s).

Production Example I-21-b Methyl 1H-5-Indazolecarboxylate

Under ice-cooling, to a solution of 910 mg of 1H-5-indazolecarboxylicacid in 60 ml tetrahydrofuran was added an excess amount of a solutionof diazomethane in diethyl ether, and the mixture was stirred at thesame temperature for 1 hour. After removing the solvent by distillation,the residue was added with 50 ml of ethyl acetate, sequentially washedwith saturated aqueous sodium hydrogencarbonate solution and brine,dried over anhydrous magnesium sulfate and the solvent was evaporated,to give 923 mg of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.87 (3H, s), 7.62 (1H, d, J=8.8 Hz), 7.92(1H, d, J=8.8 Hz), 8.26 (1H, s), 8.49 (1H, s), 13.42 (1H, s).

Production Example I-21-c 1-(tert-Butyl) 5-methyl3-bromo-1H-1,5-indazoledicarboxylate

A total of 1.43 g of the title compound was obtained as white crystalsby the procedure of Production Examples I-14-a and I-14-b, except from923 mg of methyl 1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.92 (3H, s), 8.19-8.24 (2H, m), 8.26 (1H,dd, J=1.2, 8.8 Hz).

Production Example I-21-d Methyl3-benzo[b]furan-2-yl-1H-5-indazolecarboxylate

A total of 281 mg of the title compound was obtained by the procedure ofProduction Example I-17-a, except from 700 mg of 1-(tert-butyl) 5-methyl3-bromo-1H-1,5-indazoledicarboxylate and 479 mg of2-benzo[b]furanboronic acid.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.93 (3H, s), 7.33 (1H, t, J=7.6 Hz), 7.40(1H, t, J=8.0 Hz), 7.56 (1H, s), 7.72-7.80 (3H, m), 8.03 (1H, dd, J=1.6,8.8 Hz), 8.86 (1H, s), 13.91 (1H, s).

Production Example I-21-e 3-Benzo[b]furan-2-yl-1H-5-indazolecarboxylicacid

To a solution of 275 mg of methyl3-benzo[b]furan-2-yl-1H-5-indazolecarboxylate in 3 ml methanol and 3 mltetrahydrofuran was added 1.5 ml of 5 N aqueous sodium hydroxidesolution, and the mixture was stirred at room temperature for five days.After removing the solvent by distillation, the residue was added with 9ml of 1 N hydrochloric acid, and the mixture was extracted with 200 mlof ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and the solvent was evaporated, to give 320mg of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.32 (1H, t, J=7.2 Hz), 7.39 (1H, t, J=8.0Hz), 7.54 (1H, s), 7.71 (1H, d, J=8.8 Hz), 7.84-7.79 (2H, m), 8.02 (1H,d, J=8.8 Hz), 8.85 (1H, s), 12.99 (1H, s), 13.85 (1H, s).

Production Example I-22-a Methyl3-(3-acetylphenyl)-1H-5-indazolecarboxylate

A total of 92 mg of the title compound was obtained as light browncrystals by the procedure of Production Example I-17-a, except from 355mg of 1-(tert-butyl) 5-methyl 3-bromo-1H-1,5-indazoledicarboxylateproduced in Production Example I-21-c and 246 mg of3-acetylphenylboronic acid.

¹H-NMR (400 MHz, DMSO-D₆) δ 2.69 (3H, s), 3.90 (3H, s), 7.73 (1H, d,J=8.8 Hz), 7.75 (1H, t, J=8.0 Hz), 8.01 (1H, dd, J=1.2, 8.8 Hz), 8.06(1H, dt, J=8.0, 1.2 Hz), 8.25 (1H, dt, J=8.0, 1.2 Hz), 8.50 (1H, t,J=1.2 Hz), 8.68 (1H, d, J=1.2 Hz), 13.75 (1H, s).

Production Example I-22-b 3-(3-Acetylphenyl)-1H-5-indazolecarboxylicacid

A total of 83 mg of the title compound was obtained as yellow crystalsby the procedure of Production Example I-21-e, except from 91 mg ofmethyl 3-(3-acetylphenyl)-1H-5-indazolecarboxylate.

¹H-NMR (400 MHz, DMSO-D₆) δ 2.68 (3H, s), 7.70 (1H, d, J=8.8 Hz), 7.74(1H, t, J=8.0 Hz), 7.99 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.0 Hz), 8.25(1H, d, J=8.0 Hz), 8.50 (1H, s), 8.68 (1H, s), 12.93 (1H, s), 13.70 (1H,s).

Production Example I-23-a 3-Phenyl-1H-5-indazolecarbonitrile

To a solution of 300 mg of tert-butyl3-bromo-5-cyano-1H-1-indazolecarboxylate produced in Production ExampleI-14-b in 10 ml dimethylformamide were added 376 mg oftri-n-butyl(phenyl)tin and 54 mg oftetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at150° C. for 45 minutes. After removing the solvent by distillation, theresidue was dissolved in 1.5 ml of ethyl acetate and the mixture wasadsorbed by 1.5 g of silica gel. The crude product was purified andseparated by silica gel column chromatography (ethylacetate:toluene=3:97 to 1:19) and the resulting amorphous powder wascrystallized from diisopropyl ether, to give 117 mg of the titlecompound as pale yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.46 (1H, t, J=8.0 Hz), 7.55 (2H, t, J=8.0Hz), 7.73 (1H, d, J=8.8 Hz), 7.77 (1H, d, J=8.8 Hz), 8.05 (2H, d, J=8.0Hz), 8.71 (1H, s), 13.76 (1H, s).

Production Example I-23-b 3-Phenyl-1H-5-indazolecarboxylic acid

A total of 110 mg of the title compound was obtained as pale redcrystals by the procedure of Production Example I-17-b, except from 116mg of 3-phenyl-1H-5-indazolecarbonitrile.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.46 (1H, t, J=8.0 Hz), 7.57 (2H, t, J=8.0Hz), 7.66 (1H, d, J=8.8 Hz), 7.97 (3H, d, J=8.0 Hz), 8.65 (1H, s), 12.10(1H, s), 13.56 (1H, s).

Production Example I-24-a tert-Butyl3-(3-fluorophenyl)-5-(hydroxymethyl)-1H-1-indazolecarboxylate

Under ice-cooling, a solution of 10.66 g of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ExampleI-1-c in 270 ml tetrahydrofuran was added 2.96 g of lithium aluminiumhydride, and the mixture was stirred at the same temperature for 30minutes and then heated under reflux for 7 hours. After ice-coolingagain, 0.99 g of lithium aluminium hydride was further added, and themixture was further heated under reflux for 2 hours. The reactionmixture was ice-cooled, and saturated aqueous ammonium chloride solutionwas added. Then, 200 ml of 1 N hydrochloric acid was added, and themixture was extracted with ethyl acetate for two times. The organiclayer was washed with brine, and dried over anhydrous magnesium sulfate.After filtrating the organic layer through a silica gel pat, the solventwas evaporated. After the resulting crystals were dissolved in 70 ml oftetrahydrofuran, 7.9 g of di-tert-butyl dicarbonate and 0.44 g of4-N,N-dimethylaminopyridine were added and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was added with 250 mlof ethyl acetate, sequentially washed with 1 N hydrochloric acid, water,saturated aqueous sodium hydrogencarbonate solution and brine, driedover anhydrous magnesium sulfate and the solvent was removed. Theresidue was recrystallized from ethyl acetate-diisopropyl ether, to give7.44 g of the title compound as white needles. The mother liquor wasconcentrated, and the residue was purified and separated by silica gelcolumn chromatography (ethyl acetate:toluene=1:9), to give 1.82 g of thetitle compound as yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 1.68 (9H, s), 4.68 (2H, d, J=5.6 Hz), 5.38(1H, t, J=5.6 Hz), 7.41 (1H, td, J=8.4, 2.4 Hz), 7.60-7.70 (2H, m), 7.75(1H, d, J=9.2 Hz), 7.85 (1H, d, J=8.0 Hz), 8.04 (1H, s), 8.12 (1H, d,J=8.8 Hz).

Production Example I-24-b tert-Butyl5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate

Under ice-cooling, to a solution of 3.0 g of tert-butyl3-(3-fluorophenyl)-5-(hydroxymethyl)-1H-1-indazolecarboxylate in 30 mlmethylene chloride were added 1.6 ml of triethylamine and 0.78 ml ofmethanesulfonyl chloride, and the mixture was stirred at roomtemperature for one day. To the reaction mixture was added 180 ml ofethyl acetate, and the mixture was sequentially washed with water, 1 Nhydrochloric acid, water, saturated aqueous sodium hydrogencarbonatesolution and brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated. The crude product was purified and separated bysilica gel column chromatography (toluene), to give 2.74 g of the titlecompound as yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 1.69 (9H, s), 4.99 (2H, s), 7.42 (1H, td,J=8.0, 2.4 Hz), 7.67 (1H, td, J=8.0, 6.4 Hz), 7.76 (1H, d, J=8.8 Hz),7.78 (1H, d, J=8.0 Hz), 7.86 (1H, d, J=8.0 Hz), 8.18 (1H, d, J=8.8 Hz),8.27 (1H, s).

Production Example I-24-c2-[3-(3-Fluorophenyl)-1H-5-indazolyl]acetonitrile

To a solution of 1.0 g of tert-butyl5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in 5 mldimethyl sulfoxide was added 204 mg of sodium cyanide, and the mixturewas stirred at room temperature for 50 minutes. To the reaction mixturewas added 50 ml of ethyl acetate, and after washing with water, theaqueous layer was re-extracted with diethyl ether. The collected organiclayer was sequentially washed with water (×2) and brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. The crudeproduct was purified and separated by silica gel column chromatography(ethyl acetate:toluene=1:9), and suspended in diethyl ether-diisopropylether, to give 62 mg of the title compound as yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.16 (2H, s), 7.26 (1H, td, J=8.4, 2.4 Hz),7.42 (1H, d, J=8.8 Hz), 7.59 (1H, td, J=8.0, 6.4 Hz), 7.65 (1H, d, J=8.8Hz), 7.74 (1H, d, J=10.4 Hz), 7.84 (1H, d, J=8.0 Hz), 8.12 (1H, s),13.46 (1H, s).

Production Example I-24-d 2-[3-(3-Fluorophenyl)-1H-5-indazolyl]aceticacid

50 mg of 2-[3-(3-fluorophenyl)-1H-5-indazolyl]acetonitrile was suspendedin 0.5 ml of water and 0.4 ml of concentrated sulfuric acid, and thesuspension was stirred at 95° C. for 2 hours. The reaction mixture wasadded with 20 ml of ethyl acetate, sequentially washed with water (×2)and brine, dried over anhydrous magnesium sulfate and the solvent wasevaporated, to give 48 mg of the title compound as pale red crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.74 (2H, s), 7.24 (1H, td, J=8.4, 2.4 Hz),7.32 (1H, d, J=8.8 Hz), 7.52-7.62 (2H, m), 7.74 (1H, d, J=10.4 Hz), 7.85(1H, d, J=8.0 Hz), 7.99 (1H, s), 12.31 (1H, s), 13.33 (1H, s).

Production Example I-25-a tert-Butyl3-(3-fluorophenyl)-5-formyl-1H-1-indazolecarboxylate

A total of 1.5 g of the title compound was obtained as a colorlesspowder by subjecting 1.7 g of tert-butyl3-(3-fluorophenyl)-5-(hydroxymethyl)-1H-1-indazolecarboxylate producedin Production Example I-24-a to the oxidation procedure of ProductionExample I-4-b.

¹H-NMR (400 MHz, CDCl₃) δ 1.75 (9H, s), 7.22 (1H, dt, J=2.5, 10.0 Hz),7.54 (1H, dt, J=6.1, 8.2 Hz), 7.73 (1H, dd, J=2.5, 10.0 Hz), 7.80 (1H,d, J=10.0 Hz), 8.11 (1H, dd, J=1.5, 8.8 Hz), 8.36 (1H, d, J=8.8 Hz),8.48 (1H, s), 10.14 (1H, s).

Production Example I-25-b Ethyl(E)-3-[3-(3-fluorophenyl)-1H-5-indazolyl]-2-propenoate

To a solution of 0.11 ml ethyl diethylphosphonoacetate in 5 mlN,N-dimethylformamide was added 20 mg of sodium hydride (60% oily) underice-cooling, and the mixture was stirred for 15 minutes. To the reactionmixture was added a solution of 150 mg of tert-butyl3-(3-fluorophenyl)-5-formyl-1H-1-indazolecarboxylate in 1 mlN,N-dimethylformamide, followed by stirring at room temperature for 30minutes. To the reaction mixture was added water and the mixture wasextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous magnesium sulfate and the solvent was evaporated.The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:10), to give 0.16 g of tert-butyl5-[(E)-3-ethoxy-3-oxo-1-propenyl]-3-(3-fluorophenyl)-1H-1-indazolecarboxylateas a colorless oil. This product was dissolved in 2 ml oftetrahydrofuran, 0.1 ml of 5 N hydrochloric acid was added and themixture was stirred at room temperature for 1 hour. To the reactionmixture was added saturated aqueous sodium hydrogencarbonate solution,and the mixture was extracted with ethyl acetate for two times. Theorganic layer was washed with water, dried over anhydrous magnesiumsulfate and the solvent was evaporated, to give 0.14 g of the titlecompound as a colorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.25 (3H, t, J=7.0 Hz), 4.18 (2H, q, J=7.0Hz), 6.77 (1H, d, J=16.1 Hz), 7.24 (1H, dt, J=2.4, 8.0 Hz), 7.55 (1H,dt, J=6.4, 8.0 Hz), 7.60 (1H, d, J=8.8 Hz), 7.79-7.84 (1H, m), 7.84 (1H,d, J=8.8 Hz), 7.88 (1H, d, J=16.1 Hz), 7.93 (1H, d, J=8.0 Hz), 8.48 (1H,s), 13.50-13.60 (1H, bs).

Production Example I-25-c(E)-3-[3-(3-Fluorophenyl)-1H-5-indazolyl]-2-propenoic acid

To a solution of 0.16 g of ethyl(E)-3-[3-(3-fluorophenyl)-1H-5-indazolyl]-2-propenoate in methanol wasadded 1 ml of 5 N aqueous sodium hydroxide solution, and the mixture wasstirred at room temperature for 30 minutes. The reaction mixture wasadded with diluted hydrochloric acid to be acidic and was extracted withethyl acetate for two times. The organic layer was washed with water,dried over anhydrous magnesium sulfate and the solvent was evaporated,to give 90 mg of the title compound as a colorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 6.56 (1H, d, J=16.4 Hz), 7.24 (1H, dt,J=2.2, 8.2 Hz), 7.55 (1H, dt, J=6.0, 8.2 Hz), 7.60 (1H, d, J=8.6 Hz),7.79-7.83 (1H, m), 7.81 (1H, d, J=8.8 Hz), 7.83 (1H, d, J=16.4 Hz), 7.92(1H, d, J=8.0 Hz), 8.43 (1H, s), 12.15-12.35 (1H, bs), 13.52 (1H, s).

Production Example I-26-a 3-Bromo-5-nitro-1H-indazole

To a solution of 12.4 g of 5-nitro-1H-indazole in 100 ml carbontetrachloride were added 16.2 g of N-bromosuccinimide and 0.62 g of2,2′-azobisisobutyronitrile, and the mixture was heated under reflux for1 hour. The reaction mixture was cooled, and the resulting crystals werefiltrated and washed with diethyl ether, to give 24.0 g of the titlecompound as a pale yellow powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.78 (1H, dd, J=0.5, 9.3 Hz), 8.25 (1H, dd,J=2.1, 9.3 Hz), 8.48 (1H, dd, J=0.5, 2.1 Hz).

Production Example I-26-b tert-Butyl3-bromo-5-nitro-1H-1-indazolecarboxylate

To a solution of 24.0 g of 3-bromo-5-nitro-1H-indazole and 12.2 g of4-(dimethylamino)pyridine in 50 ml tetrahydrofuran was added dropwise 23ml of di-tert-butyl carbonate at room temperature. After stirring atroom temperature for 30 minutes, the mixture was added with water,acidified by adding diluted hydrochloric acid and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and the solvent was evaporated. The residue waspurified and separated by silica gel column chromatography (ethylacetate:hexane=1:10), to give 20.5 g of the title compound as colorlessneedles.

¹H-NMR (400 MHz, CDCl₃) δ 1.73 (9H, s), 8.32 (1H, d, J=9.0 Hz), 8.46(1H, dd, J=2.3, 9.0 Hz), 8.59 (1H, d, J=2.3 Hz).

Production Example I-26-c tert-Butyl3-(3-fluorophenyl)-5-nitro-1H-1-indazolecarboxylate

To a solution of 4.5 g of tert-butyl3-bromo-5-nitro-1H-1-indazolecarboxylate in 20 ml N,N-dimethylformamidewere added 2.8 g of 3-fluorophenylboronic aid, 0.16 g of2-(di-tert-butylphosphino)biphenyl, 60 mg of palladium acetate and 2.31g of potassium fluoride, and the mixture was heated at 50° C. for twodays. To the reaction mixture was added water and the mixture wasextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous magnesium sulfate and the solvent was evaporated.The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:15), and then recrystallized fromdiisopropyl ether-hexane, to give 2.2 g of the title compound as acolorless powder.

¹H-NMR (400 MHz, CDCl₃) δ 1.76 (9H, s), 7.22-7.28 (1H, m), 7.56 (1H, dt,J=5.9, 8.0 Hz), 7.72 (1H, d, J=9.5 Hz), 7.77 (1H, d, J=8.0 Hz), 8.38(1H, d, J=9.1 Hz), 8.46 (1H, dd, J=2.0, 9.1 Hz), 8.89 (1H, d, J=2.0 Hz).

Production Example I-26-dtert-Butyl-5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate

To a solution of 180 mg of tert-butyl3-(3-fluorophenyl)-5-nitro-1H-1-indazolecarboxylate in 10 mltetrahydrofuran was added 100 mg of palladium (5%)-carbon, and themixture was stirred at room temperature in an atmosphere of hydrogen gasat normal pressure for 3 hours. The reaction mixture was filtratedthrough Celite and the solvent was evaporated, to give 184 mg of thetitle compound as a light brown oil.

¹H-NMR (400 MHz, CDCl₃) δ 1.73 (9H, s), 3.70-3.90 (2H, bs), 6.98 (1H,dd, J=1.9, 8.7 Hz), 7.14 (1H, dt, J=1.9, 8.1 Hz), 7.16 (1H, d, J=1.9Hz), 7.46 (1H, dt, J=6.0, 8.1 Hz), 7.67 (1H, dt, J=1.9, 9.7 Hz), 7.74(1H, d, J=8.1 Hz), 7.99 (1H, d, J=8.7 Hz).

Production Example I-27-a 3-Bromo-6-nitro-1H-indazole

To a solution of 5.0 g of 6-nitro-1H-indazole in 50 ml dimethylformamidewas added 5.73 g of N-bromosuccinimide at room temperature, and themixture was stirred at the same temperature for 1 hour. After removingthe solvent by distillation, the residue was added with 250 ml of ethylacetate. The mixture was sequentially washed with half-saturated aqueoussodium hydrogencarbonate solution, water and brine, and dried overanhydrous magnesium sulfate. After filtrating the organic layer througha silica gel pat, the solvent was evaporated and the resulting crystalswere suspended in toluene, to give 6.59 g of the title compound as lightbrown crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.84 (1H, d, J=8.8 Hz), 8.01 (1H, dd, J=2.0,8.8 Hz), 8.50 (1H, d, J=2.0 Hz).

Production Example I-27-b 3-(3-Fluorophenyl)-6-nitro-1H-indazole

To a solution of 1.0 g of 3-bromo-6-nitro-1H-indazole in 10 mlN-methylpyrrolidone were added 2.0 g of (3-fluorophenyl)tri-n-butyltin,and 480 mg of tetrakis(triphenylphosphine)palladium(0), and the mixturewas stirred at 180° C. for 2 hours. To the reaction mixture was added 60ml of ethyl acetate. The mixture was sequentially washed with water (×2)and brine, dried over anhydrous magnesium sulfate and the solvent wasevaporated. The crude product was purified and separated by silica gelcolumn chromatography (ethyl acetate:toluene=1:49), to give 302 mg ofthe title compound as orange crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.30 (1H, td, J=8.8, 2.8 Hz), 7.61 (1H, td,J=8.8, 6.4 Hz), 7.79 (1H, dd, J=8.8, 1.6 Hz), 7.89 (1H, d, J=7.2 Hz),8.02 (1H, dd, J=8.8, 2.0 Hz), 8.36 (1H, d, J=8.8 Hz), 8.52 (1H, d, J=2.0Hz), 14.08 (1H, s).

Production Example I-27-c 3-(3-Fluorophenyl)-1H-6-indazolamine

To a solution of 300 mg of 3-(3-fluorophenyl)-6-nitro-1H-indazole in 5ml methanol and 2.5 ml ethyl acetate was added 60 mg of 20% palladiumhydroxide-carbon (water content: 50%), and the mixture was subjected tohydrogenation at room temperature at normal pressure for 7.5 hours.After adding 2.5 ml of ethyl acetate to the reaction mixture, thecatalyst was filtered off through Celite. The solvent was evaporated,and the crude product was suspended in ethyl acetate-diisopropyl ether,to give 142 mg of the title compound as white crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 5.72 (2H, s), 6.60 (1H, s), 6.62 (1H, d,J=8.8 Hz), 7.18 (1H, td, J=8.4, 2.4 Hz), 7.51 (1H, td, J=8.0, 6.4 Hz),7.65 (1H, d, J=10.8 Hz), 7.73 (1H, d, J=8.8 Hz), 7.77 (1H, d, J=7.6 Hz),12.62 (1H, s).

Production Example I-28-a 3-(3-Fluorophenyl)-7-nitro-1H-indazole

A total of 64 mg of the title compound was obtained as purple crystalsby the procedures of Production Examples I-27-a and I-27-b, except from1.13 g of 7-nitro-1H-indazole as a starting material.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.34 (1H, td, J=8.4, 2.4 Hz), 7.48 (1H, t,J=8.0 Hz), 7.62 (1H, q, j=7.6 Hz), 7.79 (1H, dd, J=10.4, 2.4 Hz), 7.88(1H, d, J=7.6 Hz), 8.44 (1H, d, J=8.0 Hz), 8.64 (1H, d, J=8.0 Hz), 14.20(1H, s).

Production Example I-28-b 3-(3-Fluorophenyl)-1H-7-indazolamine

A total of 57 mg of the title compound was obtained as purple crystalsby the procedure of Production Example I-27-c, except from 63 mg of3-(3-fluorophenyl)-7-nitro-1H-indazole as a starting material.

¹H-NMR (400 MHz, DMSO-D₆) δ 5.43 (2H, s), 6.53 (1H, d, J=7.2 Hz), 6.96(1H, dd, J=7.2, 8.4 Hz), 7.21 (1H, td, J=8.4, 2.8 Hz), 7.25 (1H, d,J=8.4 Hz), 7.54 (1H, q, J=7.6 Hz), 7.69 (1H, d, J=10.4 Hz), 7.81 (1H, d,J=8.0 Hz), 12.91 (1H, s).

Production Example I-29-a tert-Butyl3-(2-bromoacetyl)-5-nitro-1H-1-indazolecarboxylate

To a solution of 3.0 g of tert-butyl3-bromo-5-nitro-1H-1-indazolecarboxylate produced in Production ExampleI-26-b in 20 ml toluene were added 3.2 ml of tributyl(1-ethoxyvinyl)tinand 620 mg of tetrakis(triphenylphosphine)palladium(0), and the mixturewas heated at 100° C. in an atmosphere of nitrogen gas for 6 hours. Thereaction mixture was cooled to room temperature, and the solvent wasevaporated. To the residue was added 20 ml of tetrahydrofuran, 1.56 g ofN-bromosuccinimide was added, and the mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added aqueous sodiumthiosulfate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous magnesiumsulfate and the solvent was evaporated. The residue was purified andseparated by silica gel column chromatography (ethylacetate:hexane=1:7), to give 0.9 g of the title compound as colorlessneedles.

¹H-NMR (400 MHz, CDCl₃) δ 1.78 (9H, s), 4.80 (2H, s), 8.34 (1H, dd,J=0.6, 9.2 Hz), 8.47 (1H, dd, J=2.3, 9.2 Hz), 9.26 (1H, dd, J=0.6, 2.3Hz).

Production Example I-29-b tert-Butyl3-(imidazo[1,2-a]pyridin-2-yl)-5-nitro-1H-1-indazolecarboxylate

A total of 0.88 g of tert-butyl3-(2-bromoacetyl)-5-nitro-1H-1-indazolecarboxylate was dissolved in 10ml of tetrahydrofuran-methanol (1:1), and 240 mg of 2-aminopyridine and210 mg of sodium hydrogencarbonate were added, followed by heating underreflux for 1 hour. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The mixture was washed withwater, dried over magnesium sulfate and the solvent was removed. Theresidue was purified and separated by silica gel column chromatography(ethyl acetate:hexane=1:7), to give 0.38 g of the title compound as apale yellow powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.69 (9H, s), 7.02 (1H, t, J=6.6 Hz), 7.37(1H, t, J=6.6 Hz), 7.79 (1H, d, J=7.5 Hz), 8.30 (1H, d, J=7.5 Hz), 8.50(1H, dd, J=2.3, 7.5 Hz), 8.65 (1H, d, J=6.6 Hz), 8.71 (1H, s), 9.52 (1H,d, J=2.3 Hz).

Production Example I-29-c tert-Butyl5-amino-3-imidazo[1,2-a]pyridin-2-yl-1H-1-indazolecarboxylate

A total of 0.48 g of tert-butyl3-imidazo[1,2-a]pyridin-2-yl-5-nitro-1H-1-indazolecarboxylate wassubjected to treatment by the procedure of Production Example I-26-d,and purified and separated by silica gel column chromatography (ethylacetate:hexane=1:7), to give 0.11 g of the title compound as a lightbrown powder.

¹H-NMR (400 MHz, CDCl₃) δ 1.74 (9H, s), 6.84 (1H, t, J=6.7 Hz), 6.98(1H, dd, J=2.4, 8.9 Hz), 7.22 (1H, dd, J=6.7, 8.9 Hz), 7.71 (1H, d,J=8.9 Hz), 7.93 (1H, d, J=8.9 Hz), 7.95 (1H, d, J=2.4 Hz), 8.19 (1H, d,J=6.7 Hz), 8.33 (1H, s).

Production Example I-30-a tert-Butyl5-(azidomethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate

To a solution of 600 mg of tert-butyl5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-24-b in 4 ml dimethyl sulfoxide was added 162 mg ofsodium azide, and the mixture was stirred at room temperature for 50minutes. To the reaction mixture was added 25 ml of diethyl ether. Themixture was sequentially washed with water (×3) and brine, dried overanhydrous magnesium sulfate and the solvent was evaporated, to give 571mg of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 1.69 (9H, s), 4.66 (2H, s), 7.42 (1H, td,J=8.0, 2.8 Hz), 7.67 (1H, td, J=8.0, 6.0 Hz), 7.70 (1H, d, J=8.4 Hz),7.77 (1H, d, J=10.0 Hz), 7.87 (1H, d, J=8.0 Hz), 8.19 (1H, d, J=8.0 Hz),8.21 (1H, s).

Production Example I-30-b tert-Butyl5-(aminomethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate

To a solution of 550 mg of tert-butyl5-(azidomethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in a mixtureof 10 ml ethanol and 5 ml tetrahydrofuran was added 110 mg of 5%palladium-calcium carbonate, and the mixture was hydrogenated at roomtemperature at normal pressure for 1.5 hours. After filtering off thecatalyst through Celite, the solvent was evaporated. The crude productwas purified and separated by silica gel column chromatography (ethylacetate:methanol=1:0 to 9:1), to give 427 mg of the title compound aslight green crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 1.68 (9H, s), 1.99 (2H, s), 3.89 (2H, s),7.40 (1H, td, J=8.8, 2.8 Hz), 7.64 (1H, d, J=8.4 Hz), 7.65 (1H, td,J=8.0, 6.4 Hz), 7.78 (1H, d, J=10.0 Hz), 7.87 (1H, d, J=8.4 Hz), 8.07(1H, s), 8.09 (1H, d, J=8.8 Hz).

Production Example I-30-c [3-(3-Fluorophenyl)-1H-5-indazolyl]methanamine

To a solution of 300 mg of tert-butyl5-(aminomethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in 1 mlmethylene chloride was added 2 ml of trifluoroacetic acid, and themixture was stirred at room temperature for 6.5 hours. After removingthe solvent by filtration, to the residue was added 20 ml of ethylacetate. The mixture was sequentially washed with saturated aqueoussodium hydrogencarbonate solution (×2) and brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated, to give 188 mg of thetitle compound as yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.90 (2H, s), 7.24 (1H, td, J=8.4, 2.4 Hz),7.40 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=8.4 Hz), 7.57 (1H, td, J=8.0, 6.4Hz), 7.76 (1H, d, J=10.4 Hz), 7.87 (1H, d, J=8.0 Hz), 8.05 (1H, s),13.30 (1H, s).

Production Example I-31 tert-Butyl3-(3-fluorophenyl)-5-(iodomethyl)-1H-1-indazolecarboxylate

To a solution of 500 mg of tert-butyl5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-24-b in 2.5 ml acetone was added 218 mg of sodiumiodide, and the mixture was stirred at room temperature for 2 hours.After filtering off the resulting sodium chloride through Celite, thesolvent was evaporated, to give 638 mg of the title compound as brightyellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 1.68 (9H, s), 4.87 (2H, s), 7.42 (1H, td,J=8.4, 2.8 Hz), 7.67 (1H, td, J=8.0, 6.4 Hz), 7.70-7.78 (2H, m), 7.87(1H, d, J=8.4 Hz), 8.11 (1H, d, J=8.8 Hz), 8.28 (1H, s).

Production Example I-32-a Methyl3-(3-fluorophenyl)-1-trityl-1H-5-indazolecarboxylate

To a solution of 2.43 g of methyl3-(3-fluorophenyl)-1H-5-indazolecarboxylate produced in ProductionExample I-4-e in 25 ml tetrahydrofuran was added 720 mg of 60% sodiumhydride (oily), and the mixture was stirred under ice-cooling for 10minutes. Then, 3.26 g of chlorotriphenylmethane was added and themixture was stirred at the same temperature for 30 minutes and at roomtemperature for 1 hour. The reaction mixture was ice-cooled, saturatedaqueous sodium hydrogencarbonate solution was added, and the mixture wasextracted with 100 ml of ethyl acetate. The organic layer wassequentially washed with water and brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated. The residue was crystallizedfrom ethyl acetate-diisopropyl ether, to give 3.48 g of the titlecompound as white crystals. In addition, the mother liquor wasconcentrated, and then the residue was crystallized from diisopropylether, to give 0.37 g of the title compound as white crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.85 (3H, s), 6.58 (1H, d, J=8.8 Hz), 7.22(6H, d, J=6.8 Hz), 7.28-7.40 (10H, m), 7.58-7.64 (2H, m), 7.68 (1H, dd,J=9.2, 1.2 Hz), 7.74 (1H, d, J=7.6 Hz), 8.62 (1H, s).

Production Example I-32-b[3-(3-Fluorophenyl)-1-trityl-1H-5-indazolyl]methanol

Under ice-cooling, a solution of 3.85 g of methyl3-(3-fluorophenyl)-1-trityl-1H-5-indazolecarboxylate in 40 mltetrahydrofuran was added 535 mg of lithium aluminium hydride, and themixture was stirred at the same temperature for 5 minutes and at roomtemperature for further 30 minutes. The reaction mixture was ice-cooled,saturated aqueous sodium sulfate solution was added, aluminium hydroxidewas precipitated, and the organic layer was decanted. To the residue wasadded 20 ml of tetrahydrofuran, stirred, and the organic layer wasre-decanted twice. The solvent was evaporated from the collected organiclayers. The residue was dissolved in 80 ml of ethyl acetate, and thenthe mixture was sequentially washed with water and brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. Theresulting crude crystals were recrystallized from diisopropyl ether, togive 3.37 g of the title compound as white needles.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.55 (2H, d, J=6.0 Hz), 5.18 (1H, t, J=6.0Hz), 6.43 (1H, d, J=8.8 Hz), 7.07 (1H, d, J=8.8 Hz), 7.21 (6H, d, J=6.8Hz), 7.27-7.40 (10H, m), 7.52-7.62 (2H, m), 7.74 (1H, d, J=7.6 Hz), 8.01(1H, s).

Production Example I-32-c5-(Chloromethyl)-3-(3-fluorophenyl)-1-trityl-1H-indazole

Under ice-cooling, a solution of 1.21 g of[3-(3-fluorophenyl)-1-trityl-1H-5-indazolyl]methanol in 12 ml methylenechloride were added 0.45 ml of triethylamine and 0.23 ml ofmethanesulfonyl chloride, and the mixture was stirred at roomtemperature overnight. To the reaction mixture was added 150 ml of ethylacetate. The mixture was sequentially washed with water, saturatedaqueous sodium hydrogencarbonate solution and brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. Theresulting crude crystals were recrystallized from diisopropyl ether, togive 1.13 g of the title compound as white crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.87 (2H, s), 6.49 (1H, d, J=8.8 Hz), 7.18(1H, d, J=8.8 Hz), 7.21 (6H, d, J=6.8 Hz), 7.25-7.40 (10H, m), 7.56 (1H,td, J=8.0, 7.2 Hz), 7.62 (1H, d, J=10.0 Hz), 7.75 (1H, d, J=7.6 Hz),8.24 (1H, s).

Production Example I-33 tert-Butyl5-(hydroxymethyl)-3-(2-naphthyl)-1H-1-indazolecarboxylate

A total of 3.7 g of the title compound was obtained as colorlesscrystals by the procedure of Production Example I-24-a, except from, asa starting material, 4.1 g of methyl3-(2-naphthyl)-1H-5-indazolecarboxylate produced in Production ExampleI-12-a.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.69 (9H, s), 4.69 (2H, d, J=5.5 Hz), 5.37(1H, t, J=5.5 Hz), 7.61 (1H, d, J=9.6 Hz), 7.61 (1H, ddd, J=1.3, 3.2,9.6 Hz), 7.64 (1H, dd, J=1.6, 8.5 Hz), 7.99-8.03 (1H, m), 8.08-8.12 (1H,m), 8.11 (1H, d, J=1.6 Hz), 8.14 (1H, d, J=8.5 Hz), 8.14-8.17 (1H, m),8.17-8.19 (1H, m), 8.58 (1H, bs).

Production Example I-34[3-(3-Fluorophenyl)-1-(methoxymethyl)-1H-5-indazolyl]methanol

A total of 1.0 g of methyl 3-(3-fluorophenyl)-1H-5-indazolecarboxylateobtained in Production Example I-4-e was dissolved in 15 ml ofN,N-dimethylformamide, and 200 mg of sodium hydride (60% oily) was addedunder ice-cooling, followed by stirring for 30 minutes. To the reactionmixture was added 0.4 ml of chloromethyl methyl ether, followed bystirring at room temperature for 30 minutes. To the reaction mixture wasadded water and the mixture was extracted with ethyl acetate for twotimes. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and the solvent was evaporated. The residue waspurified and separated by silica gel column chromatography (ethylacetate:hexane=1:10), to give 0.95 g of methyl3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolecarboxylate ascolorless needles. This compound was dissolved in 15 ml oftetrahydrofuran, and 8.0 ml of a solution of diisobutylaluminum hydridein toluene was added dropwise at room temperature. While cooling thereaction mixture, water was added. The mixture was acidified withdiluted hydrochloric, and extracted with ethyl acetate for two times.The organic layer was washed with sodium hydrogencarbonate and water,dried over anhydrous magnesium sulfate and the solvent was evaporated,to give 0.78 g of the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.36 (3H, s), 4.85 (2H, d, J=5.0 Hz), 5.76(2H, s), 7.11 (1H, dt, J=2.8, 8.3 Hz), 7.48 (1H, dt, J=6.5, 8.3 Hz),7.50 (1H, d, J=8.9 Hz), 7.62 (1H, d, J=8.9 Hz), 7.68 (1H, d, J=10.9 Hz),7.77 (1H, d, J=8.9 Hz), 8.00 (1H, s).

Production Example I-35-a 3-Bromo-1H-indazole

A total of 1.58 g of the title compound was obtained as beige crystalsby the procedure of Production Example I-14-a, except from 1.00 g of1H-indazole.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.23 (1H, tt, J=8.0, 1.2 Hz), 7.46 (1H, tt,J=8.0, 1.2 Hz), 7.58 (1H, dd, J=8.0, 1.2 Hz).

Production Example I-35-b 3-(3-Fluorophenyl)-1H-indazole

A total of 42 mg of the title compound was obtained as white crystals bythe procedure of Production Example I-27-b, except from 200 mg of3-bromo-1H-indazole.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.20-7.28 (2H, m), 7.43 (1H, td, J=8.0, 1.2Hz) 7.57 (1H, td, J=8.0, 6.0 Hz), 7.61 (1H, dd, J=8.0, 0.8 Hz), 7.75(1H, ddd, J=10.4, 2.8, 1.2 Hz), 7.86 (1H, ddd, J=8.0, 1.2, 1.2 Hz), 8.10(1H, dd, J=8.0, 0.8 Hz), 13.37 (1H, s).

Production Example I-36-a 1-(2,2-Diethoxyethoxy)-4-fluorobenzene

To a solution of 10.0 g of 4-fluorophenol and 16.1 ml ofbromoacetaldehyde diethylacetal in 100 ml dimethylformaldehyde was added18.5 g of potassium carbonate at room temperature, and the mixture wasstirred at 120° C. for two days. The reaction mixture was filteredthrough Celite, and the filtrate was diluted with ethyl acetate. Theorganic layer was sequentially washed with saturated aqueous ammoniumchloride solution and brine, dried over anhydrous magnesium sulfate andthe solvent was evaporated. The crude product was purified and separatedby silica gel column chromatography (ethyl acetate:n-hexane=0:10 to1:20), to give 17.3 g of the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 1.25 (3H, t, J=7.2 Hz), 3.58-3.67 (2H, m),3.71-3.80 (2H, m), 3.97 (2H, d, J=5.2 Hz), 4.82 (1H, t, J=5.2 Hz),6.84-6.88 (2H, m), 6.93-6.99 (2H, m).

Production Example I-36-b 5-Fluoro[b]benzofuran

To a solution of 16.0 g of 1-(2,2-diethoxyethoxy)-4-fluorobenzene in 50ml n-hexane was added 3.2 g of amberlyst 15 at room temperature. Afterthe mixture was treated in a sealed tube at 200° C. for 11 hours, theamberlyst 15 was filtered off. The solvent was evaporated, and the crudeproduct was purified and separated by silica gel column chromatography(n-hexane), to give 4.8 g of the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 6.74 (1H, dd, J=1.2, 2.4 Hz), 7.02 (1H, dt,J=2.4, 8.8 Hz), 7.25 (1H, dd, J=2.4, 8.8 Hz), 7.41-7.44 (1H, m), 7.65(1H, d, J=2.4 Hz).

Production Example I-36-c 5-Fluoro-2-benzo[b]furanboronic acid

In a nitrogen atmosphere, to a solution of 2.0 g of 5-fluorobenzofuranin 150 ml tetrahydrofuran was added 18.5 ml of a 1.59 M solution ofn-butyllithium in n-hexane at −78° C., and the mixture was stirred atthe same temperature for 10 minutes and at 0° C. for further 10 minutes.At −78° C., 3.7 ml of triethoxyborane was added, and the mixture wasstirred for 2 hours while elevating to 0° C. 30 ml of 1 N hydrochloricacid was added, stirred at room temperature for 1 hour, and then themixture was extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and the solvent wasevaporated. The crude product was purified and separated by silica gelcolumn chromatography (ethyl acetate:n-hexane=1:3 to 1:1), to give 525mg of the title compound as colorless crystals.

¹H-NMR (400 MHz, CDCl₃) δ 7.09 (1H, dt, J=2.4, 8.8 Hz), 7.29 (1H, dd,J=2.4, 8.8 Hz), 7.33 (1H, s), 7.44 (1H, dd, J=4.0, 8.8 Hz).

Production Example I-36-d 3-Iodo-5-nitro-1H-indazole

To a solution of 17.0 g of 5-nitroindazole in 100 ml dimethylformamidewas added 24.6 g of N-iodosuccinimide at room temperature, and themixture was stirred at 80° C. for 7 hours. After standing to cool, tothe reaction mixture were added 150 ml of water and 200 ml of diethylether, and the resulting crystals were collected by filtration. Thecrystals were sequentially washed with water, isopropanol and diethylether, to give 27.5 g of the title compound as colorless crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.74 (1H, d, J=9.2 Hz), 8.23 (1H, dd, J=2.4,9.2 Hz), 8.30 (1H, d, J=2.4 Hz), 12.01 (1H, brs).

Production Example I-36-e 3-Iodo-5-nitro-1-trityl-1H-indazole

To a solution of 27.5 g of 3-iodo-5-nitro-1H-indazole in 300 mltetrahydrofuran at 0° C. in an atmosphere of nitrogen gas was added 6.1g of 60% sodium hydride, and the mixture was stirred at the sametemperature for 10 minutes. To the mixture was added 39.8 g of tritylchloride, followed by stirring at room temperature for 1 hour. Water wasadded and the mixture was diluted with ethyl acetate. The organic layerwas sequentially washed with saturated aqueous ammonium chloridesolution and brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated. The resulting crude crystals were washed withdiethyl ether, to give 48:5 g of the title compound as colorlesscrystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 6.42 (1H, d, J=9.2 Hz), 7.13-7.32 (15H, m),7.89 (1H, ddd, J=0.4, 2.4, 9.2 Hz), 8.44 (1H, d, J=2.4 Hz).

Production Example I-36-f3-(5-Fluoro[b]benzofuran-2-yl)-5-nitro-1-trityl-1H-indazole

A total of 255 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example I-26-c, except from 500mg of 3-iodo-5-nitro-1-trityl-1H-indazole and 178 mg of5-fluoro-2-benzo[b]furanboronic acid.

¹H-NMR (400 MHz, CDCl₃) δ 6.49 (1H, dd, J=0.8, 9.2 Hz), 7.08 (1H, dt,J=2.4, 9.2 Hz), 7.15-7.36 (17H, m), 7.59 (1H, dd, J=4.0, 9.2 Hz), 7.90(1H, dd, J=2.4, 9.2 Hz), 9.25 (1H, dd, J=0.8, 2.4 Hz).

Production Example I-36-g3-(5-Fluoro[b]benzofuran-2-yl)-1-trityl-1H-indazol-5-ylamine

A total of 178 mg of the title compound was obtained as colorlesscrystals by the procedure of Production Example I-26-d, except from 250mg of 3-(5-fluorobenzo[b]furan-2-yl)-5-nitro-1-trityl-1H-indazole as astarting material.

¹H-NMR (400 MHz, CDCl₃) δ 3.67 (2H, brs), 6.25 (1H, dd, J=0.8, 9.2 Hz),6.49 (1H, dd, J=2.4, 9.2 Hz), 6.97 (1H, dt, J=2.4, 9.2 Hz), 7.02 (1H, d,J=0.8 Hz), 7.20 (1H, dd, J=2.4, 9.2 Hz), 7.20-7.31 (15H, m), 7.45 (1H,d, J=2.4 Hz), 7.47 (1H, dd, J=4.0, 9.2 Hz).

Example I-1N5-(3-Pyridylmethyl)-3-(4-fluorophenyl)-1H-5-indazolecarboxamide

To a solution of 150 mg of 3-(4-fluorophenyl)-1H-5-indazolecarboxylicacid produced in Production Example I-14 in 2.5 ml dimethylformamidewere added a solution of 70 mg of 3-picolylamine in 0.5 mldimethylformamide and 124 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (═WSC.HCl),and the mixture was stirred at room temperature for four days. Afterremoving the solvent by distillation, the residue was dissolved in 25 mlof ethyl acetate. The mixture was sequentially washed with water andbrine, dried over anhydrous magnesium sulfate and the solvent wasremoved. The resulting crude crystals were recrystallized from ethylacetate-diisopropyl ether, to give 109 mg of the title compound as paleyellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.55 (1H, d, J=5.6 Hz), 7.34-7.44 (3H, m),7.65 (1H, d, J=8.8 Hz), 7.75 (1H, d, J=7.2 Hz), 7.96 (1H, d, J=8.8 Hz),8.07 (2H, dd, J=5.6, 8.8 Hz), 8.46 (1H, d, J=8.0 Hz), 8.58 (1H, s), 8.61(1H, s), 9.23 (1H, t, J=5.6 Hz), 13.49 (1H, s).

Example I-2N5-(3-Pyridylmethyl)-3-(3-chlorophenyl)-1H-5-indazolecarboxamide

A total of 36 mg of the title compound was obtained as white needles bythe procedure of Example I-1, except from 60 mg of3-(3-chlorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-15 and 35 mg of 3-picolylamine.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.56 (1H, d, J=5.6 Hz), 7.36 (1H, dd, J=4.8,8.0 Hz), 7.51 (1H, d, J=8.0 Hz), 7.61 (1H, t, J=8.0 Hz), 7.66 (1H, d,J=8.8 Hz), 7.76 (1H, d, J=8.0 Hz), 7.97 (1H, d, J=8.0 Hz), 8.02 (1H, s),8.03 (1H, d, J=8.8 Hz), 8.46 (1H, dd, J=1.6, 4.8 Hz), 8.59 (1H, d J=1.6Hz), 8.62 (1H, s), 9.26 (1H, t, J=5.6 Hz), 13.62 (1H, s).

Example I-3N5-(3-Pyridylmethyl)-3-[3-(trifluoromethyl)phenyl]-1H-5-indazolecarboxamide

A total of 28 mg of the title compound was obtained as white crystals bythe procedure of Example I-1, except from 53 mg of3-[3-(trifluoromethyl)phenyl]-1H-5-indazolecarboxylic acid produced inProduction Example I-16 and 28 mg of 3-picolylamine.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.56 (2H, d, J=6.0 Hz), 7.37 (1H, dd, J=4.8,8.0 Hz), 7.69 (1H, d, J=8.8 Hz), 7.76 (1H, d, J=8.0 Hz), 7.79-7.87 (2H,m), 7.98 (1H, d, J=8.8 Hz), 8.28 (1H, s), 8.38 (1H, d, J=6.0 Hz), 8.46(1H, d, J=4.8 Hz), 8.59 (1H, s), 8.64 (1H, s), 9.26 (1H, t, J=6.0 Hz),13.69 (1H, s).

Example I-4N5-(3-Pyridylmethyl)-3-(3-methoxyphenyl)-1H-5-indazolecarboxamide

A total of 8 mg of the title compound was obtained as a white amorphouspowder by the procedure of Example I-1, except from 14 mg of3-(3-methoxyphenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-18 and 12 mg of 3-picolylamine.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.56 (2H, d, J=5.6 Hz), 7.02 (1H, d, J=8.0Hz), 7.37 (1H, dd, J=4.8, 7.6 Hz), 7.48 (1H, t, J=8.0 Hz), 7.53 (1H, s),7.62 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=8.0 Hz), 7.75 (1H, d, J=7.6 Hz),7.95 (1H, d, J=8.4 Hz), 8.46 (1H, d, J=4.8 Hz), 8.58 (1H, s), 8.62 (1H,s), 9.26 (1H, t, J=5.6 Hz), 13.49 (1H, s).

Example I-5N5-[(1S)-1-(Hydroxymethyl)-2-methylpropyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 50 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-1, except from 150 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 1.2 ml of 0.5 M solution of valinol in acetonitrile asstarting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 0.90 (3H, d, J=8.0 Hz), 0.92 (3H, d, J=8.0Hz), 1.88-2.00 (1H, m), 3.48-3.60 (2H, m), 3.78-3.87 (1H, m), 4.55-4.66(1H, m), 7.23-7.30 (1H, m), 7.56-7.65 (1H, m), 7.62 (1H, d, J=8.4 Hz),7.80 (1H, d, J=10.1 Hz), 7.86-7.96 (2H, m), 8.15 (1H, d, J=8.4 Hz), 8.54(1H, s)

Example I-6N5-[(1R)-2-Hydroxy-1-phenylethyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 20 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-1, except from 50 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 30 mg of R(−)-2-phenylglycinol as starting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.64-3.79 (2H, m), 4.88 (1H, t, J=6.0 Hz),5.12 (1H, dt, J=5.7, 8.2 Hz), 7.19-7.24 (1H, m), 7.28 (1H, dt, J=2.4,8.2 Hz), 7.29-7.34 (2H, m), 7.38-7.42 (2H, m), 7.61 (1H, dt, J=6.3, 8.2Hz), 7.64 (1H, d, J=8.9 Hz), 7.80 (1H, d, J=10.1 Hz), 7.90 (1H, d, J=7.7Hz), 7.95 (1H, d, J=8.9 Hz), 8.61 (1H, s), 8.84 (1H, d, J=8.2 Hz), 13.57(1H, s)

Example I-7N5-[(1S)-2-Hydroxy-1-phenethyl]-3-benzo[b]thiophen-3-yl-1H-5-indazolecarboxamide

To a solution of 50 mg of3-benzo[b]thiophen-3-yl-1H-5-indazolecarboxylic acid produced inProduction Example I-19 in 4 ml dimethylformamide were added 28 mg of(2S)-2-amino-2-phenyl-1-ethanol, 39 mg of 1-hydroxybenzotriazolemonohydrate, and 49 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, and the mixture was stirred at room temperature for fivedays. To the reaction mixture was added 40 ml of ethyl acetate, and themixture was sequentially washed with water, 1 N hydrochloric acid,water, saturated aqueous sodium hydrogencarbonate solution and brine,dried over anhydrous magnesium sulfate and the solvent was removed. Theresulting crude crystals were recrystallized from ethyl acetate-diethylether, to give 46 mg of the title compound as pale red crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.66-3.81 (2H, m) 5.00 (1H, t, J=5.6 Hz),5.16 (1H, td, J=8.0, 5.6 Hz), 7.24 (1H, t, J=7.6 Hz), 7.33 (2H, t, J=7.6Hz), 7.42 (2H, d, J=7.6 Hz), 7.45-7.55 (2H, m), 7.68 (1H, d, J=8.8 Hz),7.99 (1H, d, J=8.4 Hz), 8.11 (1H, d, J=8.8 Hz), 8.50 (1H, s), 8.65-8.70(2H, m), 8.81 (1H, d, J=8.0 Hz), 13.55 (1H, s).

Example I-8N5-[1-(Hydroxymethyl)cyclopentyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 16 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-7, except from 180 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 115 mg of 1-amino-1-cyclopentanemethanol as startingmaterials.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.51-1.60 (2H, m), 1.63-1.72 (2H, m),1.72-1.80 (2H, m), 1.97-2.07 (2H, m), 3.60 (2H, d, J=6.1 Hz), 4.87 (1H,t, J=6.1 Hz), 7.26 (1H, dt, J=2.7, 8.7 Hz), 7.59 (1H, dt, J=6.3, 7.9Hz), 7.59 (1H, d, J=8.6 Hz), 7.80 (1H, ddd, J=1.6, 2.7, 10.5 Hz), 7.94(1H, s), 8.49 (1H, s), 13.51 (1H, s)

Example I-9N5-(2-Hydroxy-2-phenylethyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 75 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-7, except from 180 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 137 mg of 2-amino-1-phenylethanol as starting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.30-3.37 (1H, m), 3.51 (1H, ddd, J=4.6,5.8, 13.2 Hz), 4.80 (1H, dd, J=4.6, 8.3 Hz), 5.56 (1H, d, J=4.6 Hz),7.21-7.26 (1H, m), 7.28 (1H, dt, J=2.4, 8.4 Hz), 7.30-7.35 (2H, m),7.36-7.40 (2H, m), 7.60 (1H, dt, J=6.3, 8.4 Hz), 7.62 (1H, d, J=9.2 Hz),7.81 (1H, d, J=10.4 Hz), 7.90 (1H, d, J=9.2 Hz), 7.90 (1H, d, J=8.4 Hz),8.54 (1H, s), 8.76 (1H, d, J=5.8 Hz), 13.54 (1H, bs)

Example I-10N5-(2-Hydroxypropyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 60 mg of the title compound was obtained as a colorless oilysubstance by the procedure of Example I-7, except from 180 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 0.08 ml of 1-amino-2-propanol as starting materials.

¹H-NMR (400 MHz, CDCl₃) δ 1.29 (3H, d, J=5.0 Hz), 3.38 (1H, ddd, J=4.9,7.4, 14.0 Hz), 3.73 (1H, ddd, J=3.0, 6.5, 14.0 Hz), 4.06-4.13 (1H, m),6.75-6.81 (1H, m), 7.14 (1H, dt, J=2.5, 8.1 Hz), 7.49 (1H, dt, J=6.2,8.1 Hz), 7.55 (1H, d, J=8.8 Hz), 7.68 (1H, ddd, J=1.4, 2.5, 9.7 Hz),7.76 (1H, d, J=8.1 Hz), 7.86 (1H, dd, J=1.8, 8.8 Hz), 8.49 (1H, d, J=1.8Hz)

Example I-11N5-[1-(4-Chlorophenyl)-2-hydroxyethyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 55 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-7, except from 180 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 112 mg of 2-amino-2-(4-chlorophenyl)-1-ethanol asstarting materials.

¹H-NMR (400 MHz, CDCl₃) δ 4.03 (1H, dd, J=5.4, 11.4 Hz), 4.07 (1H, dd,J=4.1, 11.4 Hz), 5.30 (1H, ddd, J=4.1, 5.4, 11.4 Hz), 7.02 (1H, d, J=7.0Hz), 7.14 (1H, dt, J=2.3, 8.0 Hz), 7.36 (4H, s), 7.49 (1H, dt, J=6.0,8.0 Hz), 7.56 (1H, d, J=8.7 Hz), 7.68 (1H, ddd, J=1.5, 2.3, 9.9 Hz),7.76 (1H, d, J=8.0 Hz), 7.87 (1H, dd, J=1.7, 8.7 Hz), 8.55 (1H, d, J=1.7Hz)

Example I-12N5-{2-Hydroxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 80 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-7, except from 162 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 130 mg of2-amino-2-[4-(trifluoromethyl)phenyl]-1-ethanol as starting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.66-3.83 (2H, m), 5.07 (1H, t, J=5.5 Hz),5.12-5.22 (1H, m), 7.28 (1H, dt, J=2.5, 8.7 Hz), 7.58-7.68 (2H, m), 7.65(2H, d, J=8.2 Hz), 7.69 (2H, d, J=8.2 Hz), 7.80 (1H, bd, J=10.5 Hz),7.90 (1H, d, J=8.7 Hz), 7.94 (1H, d, J=8.8 Hz), 8.62 (1H, s), 8.94 (1H,d, J=7.8 Hz), 13.58 (1H, s)

Example I-13N5-(2,3-Dihydroxypropyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 40 mg of the title compound was obtained as a colorless oilysubstance by the procedure of Example I-7, except from 180 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 0.08 ml of 3-amino-1,2-propanediol as startingmaterials.

¹H-NMR (400 MHz, CDCl₃) δ 3.17-3.24 (1H, m), 3.24-3.40 (2H, m),3.40-3.57 (1H, m), 3.62-3.70 (1H, m), 4.59 (1H, bs), 4.86 (1H, bs), 7.27(1H, dt, J=2.2, 8.4 Hz), 7.60 (1H, dt, J=6.3, 8.4 Hz), 7.63 (1H, d,J=9.0 Hz), 7.81 (1H, d, J=10.1 Hz), 7.91 (1H, d, J=8.4 Hz), 7.93 (1H, d,J=9.0 Hz), 8.59 (1H, s), 8.65 (1H, t, J=5.6 Hz)

Example I-14N5-[1-(2-Fluorophenyl)-2-hydroxyethyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

A total of 51 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-7, except from 180 mg of3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in ProductionExample I-4 and 155 mg of 2-(2-fluorophenyl)glycinol as startingmaterials.

¹H-NMR (400 MHz, CDCl₃) δ 3.66 (1H, dd, J=5.3, 11.0 Hz), 3.72 (1H, dd,J=8.0, 11.0 Hz), 5.10 (1H, t, J=6.0 Hz), 5.41 (1H, ddd, J=5.3, 8.0, 8.1Hz), 7.13-7.19 (2H, m), 7.25-7.31 (2H, m), 7.50 (1H, dt, J=2.4, 7.9 Hz),7.62 (1H, dt, J=6.3, 7.9 Hz), 7.64 (1H, d, J=8.9 Hz), 7.80 (1H, ddd,J=1.6, 2.4, 10.5 Hz), 7.90 (1H, d, J=7.9 Hz), 7.94 (1H, dd, J=1.6, 9.0Hz), 8.62 (1H, s), 8.90 (1H, d, J=8.1 Hz)

Example I-15 N3-[3-(3-Fluorophenyl)-1H-5-indazolyl]nicotinamide

To a solution of 100 mg of tert-butyl5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-26 and 0.1 ml of triethylamine in 5 mltetrahydrofuran was added 55 mg of nicotinic acid chloridehydrochloride, and the mixture was stirred at room temperature for twodays. After the completion of the reaction, the reaction mixture wastreated with 5 N hydrochloric acid by the procedure of ProductionExample I-25-b, to give 62 mg of the title compound as a colorlesspowder.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.24 (1H, dt, J=2.4, 8.3 Hz), 7.55-7.63 (3H,m), 7.69 (1H, ddd, J=1.7, 2.4, 10.2 Hz), 7.79 (1H, s), 7.80 (1H, d,J=8.3 Hz), 8.32 (1H, dt, J=1.9, 8.1 Hz), 8.57 (1H, s), 8.76 (1H, dd,J=1.9, 5.0 Hz), 9.14 (1H, d, J=2.4 Hz) 10.53 (1H, s), 13.39 (1H, s)

Example I-16N1-[3-(3-Fluorophenyl)-1H-5-indazolyl]-2-(2-thienyl)acetamide

A total of 20 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-15, except from 120 mg oftert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate producedin Production Example I-26 and 0.05 ml of 2-thiopheneacetic acidchloride as starting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 4.01 (2H, s), 7.06-7.13 (3H, m), 7.34 (1H,dd, J=1.8, 4.6 Hz), 7.38 (1H, dd, J=1.6, 8.6 Hz), 7.41 (1H, bs), 7.45(1H, d, J=8.6 Hz), 7.47 (1H, dt, J=6.0, 7.8 Hz), 7.64 (1H, d, J=9.9 Hz),7.72 (1H, d, J=7.8 Hz), 8.20 (1H, d, J=1.6 Hz)

Example I-17N1-[3-(3-Fluorophenyl)-1H-5-indazolyl]-2-(4-pyridyl)acetamide

A solution of 50 mg of tert-butyl5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-26, 26 mg of 4-pyridylacetic acid hydrochloride and0.05 ml of triethylamine in 5 ml tetrahydrofuran was added 37 mg of1,1′-carbonyldiimidazole as a condensing agent at room temperature.After the completion of the reaction, the reaction mixture was treatedwith 5 N hydrochloric acid by the procedure of Production ExampleI-25-b, to give 11 mg of the title compound as a colorless powder.

¹H-NMR (400 MHz, DMS-d₆) δ 3.73 (2H, s), 7.15 (1H, dd, J=1.8, 9.1 Hz),7.20-7.27 (1H, m), 7.30 (2H, d, J=8.8 Hz), 7.48 (2H, d, J=8.8 Hz),7.55-7.60 (5H, m), 10.03 (1H, bs), 13.35 (1H, s)

Example I-18 N-[3-(3-Fluorophenyl)-1H-5-indazolyl]methanesulfonamide

A solution of 50 mg of tert-butyl5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-26 in 2 ml tetrahydrofuran were added 30 μl oftriethylamine and 15 μl of methanesulfonyl chloride, and the mixture wasstirred at room temperature for 10 hours. The reaction mixture wasdiluted with water and was extracted with ethyl acetate. The organiclayer was sequentially washed with 1 N hydrochloric acid, water,saturated aqueous sodium hydrogencarbonate solution and brine, driedover anhydrous magnesium sulfate and the solvent was removed. Theresulting crude crystals were recrystallized from ethyl acetate-diethylether, to give 26 mg of the title compound as a colorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 2.92 (3H, s), 7.24 (1H, dt, J=2.7, 8.8 Hz),7.33 (1H, dd, J=1.8, 8.8 Hz), 7.57 (1H, t, J=7.5 Hz), 7.59 (1H, d, J=8.8Hz), 7.65 (1H, d, J=10.4 Hz), 7.78 (1H, d, J=7.5 Hz), 7.86 (1H, d, J=1.8Hz), 13.40 (1H, bs)

Example I-19N1-[3-(3-Fluorophenyl)-1H-5-indazolyl]-2,2,2-trifluoro-1-ethanesulfonamide

A total of 26 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-18, except from 50 mg of tert-butyl5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-26 and 0.02 ml of 2,2,2-trifluoro-1-ethanesulfonylchloride as starting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 4.48 (2H, q, J=10.0 Hz), 7.24 (1H, dt,J=2.6, 8.0 Hz), 7.31 (1H, dd, J=1.8, 8.9 Hz), 7.58 (1H, dt, J=5.8, 8.0),7.61 (1H, d, J=8.9 Hz), 7.67 (1H, ddd, J=1.5, 2.6, 10.1 Hz), 7.76 (1H,d, J=8.0 Hz), 7.87 (1H, d, J=1.8 Hz), 10.29 (1H, bs), 13.42 (1H, s)

Example I-20N1-[3-(3-Fluorophenyl)-1H-5-indazolyl]-4-methyl-1-benzenesulfonamide

A total of 35 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-18, except from 50 mg of tert-butyl5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-26 and 30 mg of p-toluenesulfonyl chloride asstarting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 2.28 (3H, s), 7.15 (1H, dd, J=1.8, 9.1 Hz),7.20-7.27 (1H, m), 7.30 (2H, d, J=8.8 Hz), 7.48 (2H, d, J=8.8 Hz),7.55-7.60 (5H, m), 10.03 (1H, bs), 13.35 (1H, s)

Example I-21N4-[3-(3-Fluorophenyl)-1H-5-indazolyl]-4-morpholinecarboxamide

A total of 30 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-18, except from 50 mg of tert-butyl5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-26 and 30 mg of 4-morpholinecarbonyl chloride asstarting materials.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.40-3.47 (4H, m), 3.58-3.63 (4H, m), 7.21(1H, dt, J=2.7, 8.5 Hz), 7.48 (1H, d, J=8.8 Hz), 7.53 (1H, dd, J=1.4,8.8), 7.56 (1H, dt, J=6.5, 8.0 Hz), 7.65 (1H, ddd, J=1.6, 2.7, 10.7 Hz),7.76 (1H, d, J=8.0 Hz), 8.14 (1H, d, J=1.4 Hz), 8.59 (1H, s), 13.21 (1H,s)

Example I-22N1-[(1R)-2-Hydroxy-1-phenylethyl]-(E)-3-[3-(3-fluorophenyl)-1H-5-indazolyl]-2-propenamide

A total of 11 mg of the title compound was obtained as a colorlesspowder by the procedure of Example I-7, except from 50 mg of(E)-[3-(3-fluorophenyl)-1H-5-indazolyl]-2-propenoic acid produced inProduction Example I-25 and 18 mg of S(+)-2-phenylglycinol as startingmaterials.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.61 (2H, t, J=5.5 Hz), 4.93 (1H, t, J=5.5Hz), 4.98 (1H, dt, J=5.5, 8.1 Hz), 6.81 (1H, d, J=15.6 Hz), 7.20-7.25(1H, m), 7.24 (1H, dt, J=2.6, 8.6 Hz), 7.28-7.36 (4H, m), 7.56 (1H, dt,J=6.0, 7.9 Hz), 7.55 (1H, dt, J=7.9, 6.2 Hz), 7.62 (1H, d, J=15.6 Hz),7.63 (1H, d, J=9.0 Hz), 7.65 (1H, d, J=9.0 Hz), 7.78 (1H, ddd, J=1.6,2.3, 10.7 Hz), 7.89 (1H, d, J=7.9 Hz), 8.30 (1H, s), 8.44 (1H, d, J=8.1Hz), 13.50 (1H, s)

Example I-23 a;3-(3-Fluorophenyl)-5-{[(3S)tetrahydro-3-furanyloxy]methyl}-1-trityl-1H-indazole

To a solution of 40 mg of (S)-3-hydroxytetrahydrofuran intetrahydrofuran was added 15 mg of 60% sodium hydride (oily) in anatmosphere of nitrogen gas, and the mixture was stirred at roomtemperature for 15 minute. To the reaction mixture were added 150 mg of5-(chloromethyl)-3-(3-fluorophenyl)-1-trityl-1H-indazole produced inProduction Example I-32 and 45 mg of sodium iodide, followed by stirringat room temperature for five days. After adding water to the reactionmixture, it was extracted with 20 ml of ethyl acetate. The organic layerwas sequentially washed with half-saturated aqueous sodium chloridesolution and brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated. The resulting crude product was purified andseparated by silica gel column chromatography (ethyl acetate:toluene=0:1to 1:9), to give 84 mg of the title compound as a white amorphouspowder.

¹H-NMR (400 MHz, DMSO-D₆) δ 1.90-1.97 (2H, m), 3.63-3.77 (4H, m),4.19-4.25 (1H, m), 4.50 (1H, d, J=15.6 Hz), 4.52 (1H, d, J=15.6 Hz),6.46 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=8.8 Hz), 7.17-7.40 (16H, m), 7.56(1H, td, J=8.0, 6.4 Hz), 7.59 (1H, d, J=10.0 Hz), 7.75 (1H, d, J=8.0Hz), 8.04 (1H, s).

b:3-(3-Fluorophenyl)-5-{[(3S)tetrahydro-3-furanyloxy]methyl}-1H-indazole

To a solution of 82 mg of3-(3-fluorophenyl)-5-{[(3S)tetrahydro-3-furanyloxy]methyl}-1-trityl-1H-indazolein 1.6 ml methylene chloride were added 0.05 ml of triisopropylsilaneand 0.4 ml of trifluoroacetic acid, and the mixture was stirred at roomtemperature for 20 minutes. To the reaction mixture was added ethylacetate. The mixture was sequentially washed with saturated aqueoussodium hydrogencarbonate solution (×2) and brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated. Then, the resultingcrude product was purified and separated by silica gel columnchromatography (ethyl acetate:toluene=1:4), to give 36 mg of the titlecompound as a viscous colorless oil.

¹H-NMR (400 MHz, DMSO-D₆) δ 1.93-2.01 (2H, m), 3.64-3.81 (4H, m),4.21-4.28 (1H, m), 4.59 (1H, d, J=15.6 Hz), 4.62 (1H, d, J=15.6 Hz),7.24 (1H, td, J=8.0, 2.4 Hz), 7.40 (1H, d, J=8.4 Hz), 7.58 (1H, td,J=8.0, 6.4 Hz), 7.59 (1H, d, J=8.4 Hz), 7.74 (1H, ddd, J=10.4, 1.6, 2.4Hz), 7.86 (1H, d, J=8.0 Hz), 8.04 (1H, s), 13.38 (1H, s).

Example I-24 N-Ethyl-N′-[3-(3-fluorophenyl)-1H-5-indazolyl]urea

To a solution of 50 mg of tert-butyl5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced inProduction Example I-26 in 5 ml tetrahydrofuran was added 0.015 ml ofethyl isocyanate, and the mixture was stirred at room temperature for 2hours. After the completion of the reaction, to the reaction mixture wasadded with 1 ml of 5 N hydrochloric acid and the mixture was stirred forfurther 1 hour. To the reaction mixture was added an aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The extract was sequentially washed with water, dried overanhydrous magnesium sulfate and the solvent was evaporated. To theresidue was added diisopropyl ether, and the mixture was filtered, togive 28 mg of the title compound as a colorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 1.05 (3H, t, J=6.5 Hz), 3.11 (2H, dq, J=5.6,6.5 Hz), 6.06 (1H, t, J=5.6 Hz), 7.21 (1H, dt, J=2.9, 8.6 Hz), 7.30 (1H,dd, J=1.7, 8.9), 7.46 (1H, d, J=8.9 Hz), 7.56 (1H, dt, J=6.0, 8.1 Hz),7.64 (1H, ddd, J=1.4, 2.9, 10.6 Hz), 7.74 (1H, d, J=8.6 Hz), 8.22 (1H,s), 8.48 (1H, s), 13.17 (1H, s)

Example I-25 a;[3-(3-Fluorophenyl)-1-(methoxymethyl)-1H-5-indazolyl](2-thienyl)methanol

A total of 700 mg of3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolylcarboxaldehyde wasobtained as a colorless oil, by subjecting 780 mg of[3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolyl]methanol producedin Production Example I-34 to the oxidation procedure of ProductionExample I-4-c.

A solution of 0.15 ml of thiophene in dry tetrahydrofuran was cooled to−78° C. in an atmosphere of nitrogen gas, 1.8 ml of a 2.5 M solution ofn-butyllithium in hexane was added dropwise, and the mixture was stirredat −20° C. for 1 hour. The reaction mixture was cooled again to −78° C.,and a solution of 0.35 g of the above-obtained3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolylcarboxaldehyde in 4ml dry tetrahydrofuran was added to the reaction mixture, followed byheating to room temperature. To the reaction mixture was added anaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with water, dried overanhydrous magnesium sulfate and the solvent was evaporated. The residuewas purified and separated by silica gel column chromatography (ethylacetate:hexane=1:6), to give 90 mg of the title compound as a colorlessoil.

¹H-NMR (400 MHz, CDCl₃) δ 3.37 (3H, s), 5.74 (2H, s), 6.24 (1H, s), 6.92(1H, dd, J=1.0, 3.4 Hz), 6.95 (1H, dd, J=3.4, 4.8 Hz), 7.11 (1H, dt,J=2.7, 8.2 Hz), 7.28 (1H, dd, J=1.0, 4.8 Hz), 7.48 (1H, dt, J=6.5, 8.2Hz), 7.54 (1H, dd, J=1.9, 9.0 Hz), 7.60 (1H, d, J=9.0 Hz), 7.69 (1H,ddd, J=1.2, 2.7, 9.9 Hz), 7.76 (1H, dt, J=1.2, 8.2 Hz), 8.12 (1H, d,J=1.9 Hz)

b; [3-(3-Fluorophenyl)-1H-5-indazolyl](2-thienyl)methanone

A total of 90 mg of[3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolyl](2-thienyl)methanolwas oxidized by the procedure of Production Example I-4-c, to give 85 mgof[3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolyl](2-thienyl)methanoneas a colorless powder. This compound was dissolved in 3 ml oftetrahydrofuran, and 1 ml of 5 N hydrochloric acid was added, followedby heating under reflux for one day. To the reaction mixture was addedaqueous sodium hydrogencarbonate solution and the mixture was extractedwith ethyl acetate. The organic layer was washed with water, dried overanhydrous magnesium sulfate and the solvent was evaporated. The residuewas purified and separated by silica gel column chromatography (ethylacetate:hexane=1:5), to give 30 mg of the title compound as colorlessneedles.

By treating 17 mg of[3-(3-fluorophenyl)-1-(hydroxymethyl)-1H-5-indazolyl](2-thienyl)methanone,a by-product formed by incomplete deprotection in the above reaction,with concentrated aqueous ammonia solution in methanol, 11 mg of thetitle compound was further obtained.

¹H-NMR (400 MHz, CDCl₃) δ 7.15 (1H, dt, J=2.6, 8.4 Hz), 7.21 (1H, dd,J=3.8, 4.9 Hz), 7.50 (1H, dt, J=6.6, 8.0 Hz), 7.64 (1H, d, J=8.9 Hz),7.67-7.72 (1H, m), 7.71 (1H, dd, J=1.0, 3.8 Hz), 7.74-7.79 (1H, m), 7.76(1H, dd, J=1.0, 4.9 Hz), 8.02 (1H, dd, J=1.4, 8.9 Hz), 8.61 (1H, d,J=1.4 Hz)

Example I-26 a; tert-Butyl3-(3-fluorophenyl)-5-[hydroxy(phenyl)methyl]-1H-1-indazolecarboxylate

A total of 30 mg of the title compound was obtained as a colorless oilby the procedure of Production Example I-25-a, except from 160 mg oftert-butyl 3-(3-fluorophenyl)-5-formyl-1H-1-indazolecarboxylate producedin Production Example I-25-a and 0.58 ml of a 1.04 N solution ofphenyllithium in cyclohexane as starting materials.

¹H-NMR (400 MHz, CDCl₃) δ 1.73 (9H, s), 6.02 (1H, bs), 6.24 (1H, s),7.17 (1H, ddt, J=1.3, 2.7, 8.5 Hz), 7.25-7.30 (1H, m), 7.32-7.37 (2H,m), 7.37-7.41 (2H, m), 7.49 (1H, dt, J=6.3, 7.8 Hz), 7.51 (1H, dd,J=1.5, 8.6 Hz), 7.72 (1H, ddd, J=1.7, 2.7, 9.7 Hz), 7.88 (1H, dd, J=1.3,7.8 Hz), 8.06 (1H, d, J=1.5 Hz), 8.13 (1H, d, J=8.6 Hz)

b; [3-(3-Fluorophenyl)-1H-5-indazolyl](phenyl)methanone

A total of 30 mg of tert-butyl3-(3-fluorophenyl)-5-[hydroxy(phenyl)methyl]-1H-1-indazolecarboxylate asa starting material was oxidized by the procedure of Production ExampleI-4-c, was treated with 5 N hydrochloric acid by the procedure ofProduction Example I-25-b, to give 4 mg of the title compound as acolorless powder.

¹H-NMR (400 MHz, DMS-d₆) δ 7.25 (1H, ddt, J=0.7, 2.7, 8.6 Hz), 7.52-7.59(3H, m), 7.64-7.70 (1H, m), 7.69 (1H, ddd, J=1.4, 2.7, 10.4 Hz), 7.74(1H, dd, J=0.7, 8.6 Hz), 7.75-7.80 (3H, m, 7.83 (1H, dd, J=1.5, 8.6 Hz),8.38 (1H, dd, J=0.7, 1.5 Hz)

Example I-27 a; (E)-3-(Dimethylamino)-1-(1H-3-indazolyl)-2-propen-1-one

A total of 5.0 g of 1H-indazole as a starting material was subjected tobromination and tert-butoxycarbonylation by the procedures of ProductionExamples I-26-a and I-26-b, was acetylated at the 3-position by theprocedure of Production Example I-29-a, to give 2.5 g of tert-butyl3-acetyl-1H-1-indazolecarboxylate. A total of 1.5 g of this product wastreated with 5 N hydrochloric acid by the procedure of ProductionExample I-25-b and thereby yielded 860 mg of 1-(1H-3-indazolyl)ethanone.A solution of 240 mg of this product and 0.4 ml of N,N-dimethylformamidedimethylacetal in 5 ml toluene was heated under reflux for 9 hours. Thesolvent was evaporated, and the residue was purified and separated bysilica gel column chromatography (ethyl acetate:hexane=2:1), to give 88mg of the title compound as a colorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 2.88 (3H, bs), 3.13 (3H, bs), 6.08 (1H, d,J=13.1 Hz), 7.19 (1H, t, J=7.6 Hz), 7.36 (1H, t, J=7.6 Hz), 7.56 (1H, d,J=7.6 Hz), 7.72 (1H, d, J=13.1 Hz), 8.26 (1H, d, J=7.6 Hz), 13.37 (1H,s)

b; 4-(1H-3-Indazolyl)-2-pyrimidinamine

A total of 20 mg of metallic sodium was dissolved in 5 ml of dryethanol. To the resulting solution were added 76 mg of guanidinehydrochloride and 85 mg of(E)-3-(dimethylamino)-1-(1H-3-indazolyl)-2-propen-1-one, followed byheating under reflux for 12 hours. To the reaction mixture was addedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was washed with water, dried overanhydrous magnesium sulfate and the solvent was evaporated. The residuewas purified and separated by silica gel column chromatography (ethylacetate:hexane=7:5), to give 55 mg of the title compound as a colorlesspowder.

¹H-NMR (400 MHz, DMSO-d₆) δ 6.69 (2H, bs), 7.22 (1H, t, J=7.9 Hz), 7.24(1H, d, J=5.3 Hz), 7.40 (1H, t, J=7.9 Hz), 7.58 (1H, d, J=7.9 Hz), 8.26(1H, d, J=5.3 Hz), 8.67 (1H, d, J=7.9 Hz)

The compounds according to Examples I-28 to I-100 were synthesized bythe following Synthesis Process I-A.

Synthesis Process I-A

A total of 96 pieces of a polystyrene resin (SunPhase PolystyreneD-Seriese, Trityl™) labeled with TRANSTEM™ was left stand in 100 ml of a10% solution of acetyl chloride in methylene chloride for 3 hours. Afterremoving the solution, the residue was washed with three portions ofmethylene chloride and dried in vacuo. The resin was heated in asolution of 15 g of 3-bromo-5-nitro-1H-indazole produced in ProductionExample I-26-a and diisopropylamine in 150 ml N-methylpyrrolidone at 80°C. for 4 hours. After removing the solution, the resin was sequentiallywashed with N-methylpyrrolidone, ethanol, water, methanol andtetrahydrofuran, and dried in vacuo.

The resulting resin was divided among 8 groups (each 12 pieces)according to its label and was added to 15 ml of a solution of 0.5 Mboronic acid in N-methylpyrrolidone of eight types previously prepared,respectively. Each reaction mixture was treated with 1.5 ml of a 0.5 Msolution of 2-(di-tert-butylphosphino)biphenyl in N-methylpyrrolidone,1.8 ml of a 8 M aqueous solution of potassium fluoride, and a catalyticamount of palladium(II) acetate by heating at 80° C. for 12 hours. Afterremoving the solution, the resin was washed according to the aboveprocedure and was dried under reduced pressure. The resin was heated in150 ml of a 2 M solution of stannic chloride in N-methylpyrrolidone at80° C. for 4 hours. After removing the solution, the resin was washedaccording to the above procedure and was dried in vacuo.

The resin was further divided among 12 groups (each 8 pieces) accordingto its label and was added to 15 ml of a solution of 0.5 M carboxylicacid in N-methylpyrrolidone of twelve types previously prepared,respectively. To each well were sequentially added 1.15 g of1-hydroxybenzotriazole monohydrate, 1.2 ml of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (═WSC) and 2.0 ml ofdiisopropylethylamine. In a sulfonamide compound, a sulfonyl chloridereagent and diisopropylethylamine were added in tetrahydrofuran. Themixture was subjected to sonication for 1 hour and was left stand atroom temperature for one day. After removing the solution, the resin waswashed according to the above procedure and was dried under reducedpressure. The resin was placed in each of 96-well pin plate according toits label.

A mixture solution of 0.5 ml of trifluoroacetic acid, 0.1 ml oftriisopropylsilane, and 0.5 ml of dichloromethane previously preparedwas added to the resin in each of the 96-well plate, and the mixture wassubjected to sonication for 10 minutes and was left stand for 30minutes. This procedure was repeated twice, and the resin was washedwith 1 ml of dimethylformamide. Next, nitrogen gas was blown to theacid-treated wells, and each residue was dissolved in adimethylformamide solution obtained in washing procedure, was purifiedand separated by LC-MS (developing solvent, (eluent); 0.1% solution oftrifluoroacetic acid in acetonitrile:0.1% aqueous solution oftrifluoroacetic acid=1:99 to 100:0/20 minute-cycle, flow rate; 20ml/min, column; YMC Combiprep ODS-AM, 20 mmΦ×50 mm (Long)), to give thefollowing compounds.

Example I-282-(5-{[2-(1,1-Dioxo-1l⁶,4-thiazinan-4-yl)acetyl]amino}-1H-3-indazolyl)benzoicacid

MS (ESI) m/z 429 MH⁺

Example I-29N7-[3-(2,3-Dihydro-1H-5-indolyl)-1H-5-indazolyl]bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxamide

MS (ESI) m/z 381 MH⁺

Example I-30 N1-[3-(8-Quinolyl)-1H-5-indazolyl]-2,4-dichlorobenzamide

MS (ESI) m/z 433 M⁺

Example I-31N1-{3-[4-(Methylsulfonyl)phenyl]-1H-5-indazolyl}-2-(2,4-dichlorophenyl)acetamide

MS (ESI) m/z 474 M⁺

Example I-32N1-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-1-cyclopentanecarboxamide

MS (ESI) m/z 362 MH⁺

Example I-33N7-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-2,3-dihydrobenzo[b]furan-7-carboxamide

MS (ESI) m/z 412 MH⁺

Example I-34N1-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-3-(2-thienyl)propanamide

MS (ESI) m/z 404 MH⁺

Example I-35N1-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-(E)-3-cyclopropyl-2-propenamide

MS (ESI) m/z 360 MH⁺

Example I-36N1-[3-(2-Naphthyl)-1H-5-indazolyl]-1-cyclopropanecarboxamide

MS (ESI) m/z 328 MH⁺

Example I-37 N2-[3-(2-Naphthyl)-1H-5-indazolyl]-2-thiophenecarboxamide

MS (ESI) m/z 370 MH⁺

Example I-38 N1-[3-(2-Naphthyl)-1H-5-indazolyl]-8-hydroxyoctanamide

MS (ESI) m/z 402 MH⁺

Example I-39N1-(3-{3-[(Cyclopropylcarbonyl)amino]phenyl}-1H-5-indazolyl)-1-cyclopropanecarboxamide

MS (ESI) m/z 361 MH⁺

Example I-40N1-3-[4-(Benzyloxy)phenyl]-1H-5-indazolyl3-oxo-1-cyclopentanecarboxamide

MS (ESI) m/z 426 MH⁺

Example I-41N1-[3-(2-Naphthyl)-1H-5-indazolyl]-4-(hydroxymethyl)benzamide

MS (ESI) m/z 394 MH⁺

Example I-42N1-[3-(2-Naphthyl)-1H-5-indazolyl]-4-methoxy-1-cyclohexanecarboxamide

MS (ESI) m/z 400 MH⁺

Example I-43N1-[3-(2-Naphthyl)-1H-5-indazolyl]-2-hydroxy-3-phenylpropanamide

MS (ESI) m/z 408 MH⁺

Example I-44N1-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-trans-4-hydroxy-1-cyclohexanecarboxamide

MS (ESI) m/z 392 MH⁺

Example I-45N1-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-2-(3-pyridyl)acetamide

MS (ESI) m/z 369 MH⁺

Example I-46N1-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-2-(3-thienyl)acetamide

MS (ESI) m/z 374 MH⁺

Example I-47N2-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxamide

MS (ESI) m/z 408 MH⁺

Example I-48 N2-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-2-furamide

MS (ESI) m/z 344 MH⁺

Example I-49 N3-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-3-furamide

MS (ESI) m/z 344 MH⁺

Example I-50N1-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-2-hydroxy-2-phenylacetamide

MS (ESI) m/z 384 MH⁺

Example I-51N1-[3-(4-Acetylphenyl)-1H-5-indazolyl]-2-(2-pyridyl)acetamide

MS (ESI) m/z 371 MH⁺

Example I-52N1-[3-(4-Acetylphenyl)-1H-5-indazolyl]-2-(3,4-dimethoxyphenyl)acetamide

MS (ESI) m/z 430 MH⁺

Example I-53 N1-[3-(2-Naphthyl)-1H-5-indazolyl]-4-oxopentanamide

MS (ESI) m/z 358 MH⁺

Example I-54N1-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-3-methoxypropanamide

MS (ESI) m/z 352 MH⁺

Example I-55N3-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)tetrahydro-3-furancarboxamide

MS (ESI) m/z 364 MH⁺

Example I-56N1-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-3-oxo-1-indancaroxamide

MS (ESI) m/z 408 MH⁺

Example I-57 N1-[3-(4-Acetylphenyl)-1H-5-indazolyl]-3-phenoxypropanamide

MS (ESI) m/z 400 MH⁺

Example I-58N1-[3-(2-Naphthyl)-1H-5-indazolyl]-3-hydroxy-2-(hydroxymethyl)-2-methylpropanamide

MS (ESI) m/z 376 MH⁺

Example I-59N1-[3-(2-Naphthyl)-1H-5-indazolyl]-2-(2-oxocyclopentyl)acetamide

MS (ESI) m/z 384 MH⁺

Example I-60N2-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-(2S)-5-oxotetrahydro-1H-2-pyrrolecarboxamide

MS (ESI) m/z 377 MH⁺

Example I-61N2-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-(2R)-5-oxotetrahydro-1H-2-pyrrolecarboxamide

MS (ESI) m/z 377 MH⁺

Example I-62N2-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)tetrahydro-2-furancarboxamide

MS (ESI) m/z 348 MH⁺

Example I-63N3-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-2,2-dimethyl-5-oxotetrahydro-3-furancarboxamide

MS (ESI) m/z 390 MH⁺

Example I-64 N-(3-Phenyl-1H-5-indazolyl)methanesulfonamide

MS (ESI) m/z 288 MH⁺

Example I-654-({[3-(3-Fluorophenyl)-1H-5-indazolyl]amino}sulfonyl)benzoic acid

MS (ESI) m/z 412 MH⁺

Example I-66N1-[5-({[3-(3-Fluorophenyl)-1H-5-indazolyl]amino}sulfonyl)-4-methyl-1,3-thiazol-2-yl]acetamide

MS (ESI) m/z 446 MH⁺

Example I-67N2-[3-(4-Methoxyphenyl)-1H-5-indazolyl]-4-(phenylsulfonyl)-2-thiphenesulfonamide

MS (ESI) m/z 526 MH⁺

Example I-68N2-[3-(1,3-Benzodioxol-5-yl)-1H-5-indazolyl]-2-propanesulfonamide

MS (ESI) m/z 360 MH⁺

Example I-69N1-[3-(2-Thienyl)-1H-5-indazolyl]-3,5-di(trifluoromethyl)-1-benzenesulfonamide

MS (ESI) m/z 492 MH⁺

Example I-70N,N-Dimethyl-N′-{3-[4-(trifluoromethyl)phenyl]-1H-5-indazolyl}sulfamide

MS (ESI) m/z 385 MH⁺

Example I-71N2-{3-[3,5-Di(trifluoromethyl)phenyl]-1H-5-indazolyl}-5-(2-pyridyl)-2-thiophenesulfonamide

MS (ESI) m/z 569 MH⁺

Example I-72 N2-[3-(2,4-Dichlorophenyl)-1H-5-indazolyl]-2-furamide

MS (ESI) m/z 372 MH⁺

Example I-73N1-[3-(3-Ethoxyphenyl)-1H-5-indazolyl]-3-hydroxy-3-methylpentanamide

MS (ESI) m/z 368 MH⁺

Example I-74N1-(3-Dibenzo[b,d]furan-4-yl-1H-5-indazolyl)-1-cyclopropanecaroxamide

MS (ESI) m/z 368 MH⁺

Example I-75N1-{3-[4-(tert-butyl)phenyl]-1H-5-indazolyl}-1-phenyl-1-cyclopropanecarboxamide

MS (ESI) m/z 410 MH⁺

Example I-76N1-[3-(2-Naphthyl)-1H-5-indazolyl]-3-hydroxy-2,2-dimethylpropanamide

MS (ESI) m/z 360 MH⁺

Example I-77 N1-{3-[3-Fluoro-4-(phenyl)phenyl}-2-oxo-2-phenylacetamide

MS (ESI) m/z 436 MH⁺

Example I-78N1-{3-[4-(trifluoromethoxy)phenyl]-1H-5-indazolyl}-4-(dimethylamino)benzamide

MS (ESI) m/z 441 MH⁺

Example I-79N1-[3-(4-Phenoxyphenyl)-1H-5-indazolyl]-3-hydroxy-3-methylbutanamide

MS (ESI) m/z 402 MH⁺

Example I-80N1-[3-(3,4-Dichlorophenyl)-1H-5-indazolyl]-(1S,2S)-2-phenylcyclopropane-1-carboxamide

MS (ESI) m/z 422 M⁺

Example I-81N7-[3-(3-Acetylphenyl)-1H-5-indazolyl]bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxamide

MS (ESI) m/z 382 MH⁺

Example I-82 N4-[3-(3-Acetylphenyl)-1H-5-indazolyl]isonicotinamide

MS (ESI) m/z 357 MH⁺

Example I-83N1-[3-(3-Acetylphenyl)-1H-5-indazolyl]-(2R)-2-amino-2-cyclohexylethanamide

MS (ESI) m/z 391 MH⁺

Example I-84N1-[3-(5-Acetyl-2-thienyl)-1H-5-indazolyl]-1-cyclobutanecarboxamide

MS (ESI) m/z 340 MH⁺

Example I-85N1-[3-(4-Biphenyl)-1H-5-indazolyl]-1-phenyl-1-cyclopentanecarboxamide

MS (ESI) m/z 458 MH⁺

Example I-86N3-[3-(3-Biphenyl)-1H-5-indazolyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide

MS (ESI) m/z 445 MH⁺

Example I-87N1-{3-[3,5-Di(trifluoromethyl)phenyl]-1H-5-indazolyl}-(2R)-2-amino-3,3-diphenylpropanamide

MS (ESI) m/z 569 MH⁺

Example I-88N1-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-(2R)-2-amino-3,3-dimethylbutanamide

MS (ESI) m/z 363 MH⁺

Example I-89N1-(3-Benzo[b]furan-2-yl-1H-5-indazolyl)-(2R)-2-amino-3-(benzyloxy)propanamide

MS (ESI) m/z 427 MH⁺

Example I-90N1-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-(2R)-2-amino-3-phenylpropanamide

MS (ESI) m/z 413 MH⁺

Example I-91N1-(3-Benzo[b]thiophen-2-yl-1H-5-indazolyl)-(2R)-2-amino-3-methylbutanamide

MS (ESI) m/z 365 MH⁺

Example I-92 N2-[3-(2-Thienyl)-1H-5-indazolyl]-2-pyridinecarboxamide

MS (ESI) m/z 321 MH⁺

Example I-93N1-[3-(2-Furyl)-1H-5-indazolyl]-3-hydroxy-2-phenylpropanamide

MS (ESI) m/z 348 MH⁺

Example I-94 N-[3-(2-Naphthyl)-1H-5-indazolyl]methanesulfonamide

MS (ESI) m/z 338 MH⁺

Example I-95 N1-[3-(2-Naphthyl)-1H-5-indazolyl]acetamide

MS (ESI) m/z 302 MH⁺

Example I-96N1-{3-[2-(trifluoromethyl)phenyl]-1H-5-indazolyl}-2-(1,3-benzodioxol-5-yl)acetamide

MS (ESI) m/z 440 MH⁺

Example I-97 N1-[3-(3-Thienyl)-1H-5-indazolyl]-2-methoxyacetamide

MS (ESI) m/z 288 MH⁺

Example I-98N1-[3-(1H-2-Pyrrolyl)-1H-5-indazolyl]-(3S)-3-hydroxy-3-phenylpropanamide

MS (ESI) m/z 347 MH⁺

Example I-99N1-[3-(2,4-Dimethoxy-5-pyrimidinyl)-1H-5-indazolyl]-2-(2-thienyl)acetamide

MS (ESI) m/z 396 MH⁺

Example I-100N1-[3-(3-Pyridyl)-1H-5-indazolyl]-(3R)-3-hydroxy-3-phenylpropanamide

MS (ESI) m/z 359 MH⁺

The compounds according to Examples I-101 to I-107 were synthesized bythe following Synthesis Process I-B.

Synthesis Process I-B

The resin was subjected to the procedures of Synthesis Process I-A tillthe treatment with stannic chloride and was divided among two groups(each 48 pieces) according to the label, followed by amidation with a0.5 M solution of any of two amino acids having an amino group protectedby Fmoc group in N-methylpyrrolidone. Each of the resin was washed andwas treated with N-methylpyrrolidone solution containing 20% piperidineto thereby remove the Fmoc group.

The resulting resin was divided among twelve groups (each 8 pieces), tengroups of which were treated with any of 0.5 M solution of five alkylbromides in N-methylpyrrolidone and cesium carbonate for alkylation ofthe amide group. Then, the resin was subjected to an acid treatmentaccording to the procedure of Synthesis Process I-A, was separated andpurified by LC-MS according to the procedure of Synthesis Process I-A,to give the following compounds.

Example I-101N2-[3-Benzo[b]furan-2-yl-1H-5-indazolyl]-(2S)-tetrahydro-1H-2-pyrrolecarboxamide

MS (ESI) m/z 347 MH⁺

Example I-102N2-[3-(5-Acetyl-2-thienyl)-1H-5-indazolyl]-(2S)-1-benzyltetrahydro-1H-2-pyrrolecarboxamide

MS (ESI) m/z 445 MH⁺

Example I-103N2-[3-(3-Ethoxyphenyl)-1H-5-indazolyl]-(2S)-1-[3-(trifluoromethyl)benzyl]tetrahydro-1H-2-pyrrolecarboxamide

MS (ESI) m/z 509 MH⁺

Example I-104 N4-[3-(2-Naphthyl)-1H-5-indazolyl]-4-piperidinecarboxamide

MS (ESI) m/z 371 MH⁺

Example I-105N4-[3-Benzo[b]thiophen-2-yl-1H-5-indazolyl]-1-benzyl-4-piperidinecarboxamide

MS (ESI) m/z 467 MH⁺

Example I-106N4-[3-(4-Acetylphenyl)-1H-5-indazolyl]-1-(2,4-difluorobenzyl)-4-piperidinecarboxamide

MS (ESI) m/z 489 MH⁺

Example I-107 Methyl{3-[4-({[3-(1-naphthyl)-1H-5-indazolyl]amino}carbonyl)piperidino]methyl}benzoate

MS (ESI) m/z 519 MH⁺

The compounds according to Examples I-108 to I-156 were synthesized bythe following Synthesis Process I-C.

Synthesis Process I-C

A solution of 180 mg of each indazolecarboxylic acid produced inProduction Examples I-1 to I-25 in 6 ml dimethylformamide was pipettedinto several test tubes in an amount of 0.5 ml each, each of which wastreated with 1.1 equivalents of any of various amines. The reactionmixture was sequentially treated with 0.065 ml of a 1 M solution of1-hydroxybenzotriazole monohydrate in dimethylformamide, 0.130 ml of a 1M solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (═WSC) indimethylformamide, and 0.05 ml of diisopropylamine, the mixture wassubjected to sonication for 10 minutes and was left stand for one day.Each of the reaction mixtures was separated and purified by LC-MS underthe conditions of Synthesis Process I-A and thereby yielded the testcompounds.

Example I-108 [3-(3-Fluorophenyl)-1H-5-indazolyl](morpholino)methanone

MS (ESI) m/z 326 MH⁺

Example I-109[3-(3-Fluorophenyl)-1H-5-indazolyl](4-methylpiperazino)methanone

MS (ESI) m/z 339 MH⁺

Example I-110[3-(3-Fluorophenyl)-1H-5-indazolyl](4-hydroxy-4-phenylpiperidino)methanone

MS (ESI) m/z 416 MH⁺

Example I-111N5-(3-morpholinopropyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 383 MH⁺

Example I-112N5-[(1S)-1-(Hydroxymethyl)-3-methylbutyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 342 MH⁺

Example I-113N5-[(1S)-2-Hydroxy-1-(1H-1-indazolylmethyl)ethyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 380 MH⁺

Example I-114N5-[(1S)-1-Benzyl-2-hydroxyethyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 390 MH⁺

Example I-115N5-[(1S)-1-(Hydroxymethyl)propyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 328 MH⁺

Example I-116N5-[(1R)-1-(Hydroxymethyl)propyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 328 MH⁺

Example I-117N5-(2-Piperidinoethyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 367 MH⁺

Example I-118N5-(trans-4-Hydroxycyclohexyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 354 MH⁺

Example I-119N5-[2-(2-Hydroxyethoxy)ethyl]-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 344 MH⁺

Example I-120N5-Ethyl-N-5-(2-hydroxyethyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 328 MH⁺

Example I-121N5-[4-(Aminosulfonyl)benzyl]-3-(2-methoxyphenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 437 MH⁺

Example I-122N5-[(1R,2R)-2-(Hydroxymethyl)cyclohexyl]-3-(2-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 368 MH⁺

Example I-123N5-[(1R,2R)-2-Hydroxycyclohexyl]-3-(2-quinolyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 387 MH⁺

Example I-124N5-[(1-(Methoxymethyl)propyl]-3-(2-quinolyl)1H-5-indazolecarboxamide

MS (ESI) m/z 375 MH⁺

Example I-125N5-[4-(Methylsulfonyl)benzyl]-3-(2-quinolyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 457 MH⁺

Example I-126N5-[(1R,2S)-2-(Hydroxymethyl)cyclohexyl]-3-(3-quinolyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 401 MH⁺

Example I-127N5-[2-(1H-3-Indolyl)ethyl]-3-(4-quinolyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 368 MH⁺

Example I-128N5-(5-Hydroxypentyl)-3-(-(1,3-benzothiazol-2-yl)-1H-5-indazolecarboxamide

MS (ESI) m/z 381 MH⁺

Example I-129 N5-Cyclopropyl-3-phenyl-1H-5-indazolecarboxamide

MS (ESI) m/z 278 MH⁺

Example I-130N5-[2-(Acetylamino)ethyl]-3-(2-naphthyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 373 MH⁺

Example I-131N5-(3-Pyridylmethyl)-3-(5-acetyl2-thienyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 377 MH⁺

Example I-132N5-[(1S)-2-Amino-1-methyl-2-oxoethyl]-3-(3-acetylphenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 373 M+Na⁺

Example I-133N6-(3-Methoxybenzyl)-3-(3-fluorophenyl)-1H-6-indazolecarboxamide

MS (ESI) m/z 376 MH⁺

Example I-134N7-[3-(1H-1-Imidazolyl)propyl]-3-(3-fluorophenyl)-1H-7-indazolecarboxamide

MS (ESI) m/z 364 MH⁺

Example I-135N1-Cyclopropyl-2-[3-(3-fluorophenyl)-1H-5-indazolyl]acetamide

MS (ESI) m/z 310 MH⁺

Example I-136N1-(3-Methoxyphenethyl)-2-[3-(3-fluorophenyl)-1H-5-indazolyl]acetamide

MS (ESI) m/z 404 MH⁺

Example I-137N5-[3-(2-Oxotetrahydro-1H-1-pyrrolyl)propyl]-3-benzo[b]thiophen-2-yl-1H-5-indazolecarboxamide

MS (ESI) m/z 419 MH⁺

Example I-138N5-[2-(2-Thienyl)ethyl]-3-benzo[b]thiophen-2-yl-1H-5-indazolecarboxamide

MS (ESI) m/z 404 MH⁺

Example I-139N5-(2-Phenoxyethyl)-3-benzo[b]furan-2-yl-1H-5-indazolecarboxamide

MS (ESI) m/z 398 MH⁺

Example I-140N5-(3-Tetrahydro-1H-1-pyrrolylpropyl)-3-benzo[b]furan-2-yl-1H-5-indazolecarboxamide

MS (ESI) m/z 389 MH⁺

Example I-141N5-[2-(1H-3-Indolyl)ethyl]-3-(2-naphthyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 431 MH⁺

Example I-142N5-(2,3-Dihydro-1H-2-indenyl))-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 372 MH⁺

Example I-143 N5-Cyclopropyl-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 296 MH⁺

Example I-144N5-(2-Furylmethyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 336 MH⁺

Example I-145N5-Tetrahydro-2-furanylmethyl-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 340 MH⁺

Example I-146N5-(2-Morpholinoethyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 369 MH⁺

Example I-147N5-(2,3-Dihydro-1,4-benzodioxin-6-yl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 390 MH⁺

Example I-148N5-[(2R)-3,4-Dihydro-2H-2-chromenylmethyl]-3-(2-pyridyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 385 MH⁺

Example I-149N5-[1-(Methoxymethyl)propyl]-3-(2-pyridyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 325 MH⁺

Example I-150N5-(1,3-Benzodioxol-5-ylmethyl)-3-(3-pyridyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 373 MH⁺

Example I-151N5-Cyclopropylmethyl-3-(2-naphthyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 342 MH⁺

Example I-152N5-[(3R)-2-Oxotetrahydro-1H-3-furanyl]-3-(2-naphthyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 372 MH⁺

Example I-153N5-[2-(2-Puryl)-2-oxoethyl]-3-(2-naphthyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 396 MH⁺

Example I-154N5-[2-((1,3-Thiazol-2-yl)ethyl]-3-(2-naphthyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 399 MH⁺

Example I-155N5-(2-Ethoxyethyl)-3-(3-fluorophenyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 328 MH⁺

Example I-156N5-[(3S)-2-Oxotetrahydro-1H-3-furanyl]-3-(2-quinolyl)-1H-5-indazolecarboxamide

MS (ESI) m/z 373 MH⁺

The compounds according to Examples I-157 to I-162 were synthesized bythe following Synthesis Process I-D.

Synthesis Process I-D

Each of the amines produced in Production Examples I-27, I-28 and I-30was dissolved in dimethylformamide to a concentration of 5 mg/ml andeach 1 ml of the solution was pipetted into test tubes. The solution wasmixed with 0.05 ml of a 0.5 M solution of any of carboxylic acids, 0.025ml of a 1 M solution of 1-hydroxybenzotriazole monohydrate indimethylformamide, and 0.05 ml of a 1 M solution of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (═WSC) indimethylformamide, each of which had been prepared, and the mixture wasstirred at room temperature overnight. A sulfonamide compound wasallowed to react with methanesulfonyl chloride in tetrahydrofuran in thepresence of triethylamine. Each of the reaction mixtures was separatedand purified by LC-MS under the conditions of Synthesis Process I-A, togive the following compounds.

Example I-157

BenzylN-((1S)-2-{[3-(3-fluorophenyl)-1H-6-indazolyl]amino}-1-methyl-2-oxoethyl)carbamate

MS (ESI) m/z 433 MH⁺

Example I-158 N1-[3-(3-Fluorophenyl)-1H-7-indazolyl]-3-phenoxybenzamide

MS (ESI) m/z 424 MH⁺

Example I-159N1-{[3-(3-Fluorophenyl)-1H-5-indazolyl]methyl}-1-cyclopropanecarboxamide

MS (ESI) m/z 310 MH⁺

Example I-160N1-{[3-(3-Fluorophenyl)-1H-5-indazolyl]methyl}-3-methoxybenzamide

MS (ESI) m/z 376 MH⁺

Example I-161N1-{[3-(3-Fluorophenyl)-1H-5-indazolyl]methyl}-3-phenoxypropanamide

MS (ESI) m/z 390 MH⁺

Example I-162N3-{[3-(3-Fluorophenyl)-1H-5-indazolyl]methyl}tetrahydro-3-furancarboxamide

MS (ESI) m/z 340 MH⁺

The compounds according to Examples I-163 to I-166 were synthesized byaccording to following Synthesis Process I-E.

Synthesis Process I-E

Each of the amines produced in Production Examples I-29 and I-36 wasdissolved in dimethylformamide to a concentration of 20 mg/ml and each0.5 ml of the solution was pipetted into test tubes. The solution wassequentially mixed with 0.08 ml of a 0.5 M solution of any of carboxylicacids in dimethylformamide, 0.1 ml of a 0.5 M solution of1-hydroxybenzotriazole monohydrate in dimethylformamide, 0.1 ml of a 1 Msolution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide indimethylformamide, and 0.05 ml of diisopropylethylamine, each of whichhad been prepared, and the mixture was left stand for one day. Thereaction mixture in the test tube was diluted with water, was extractedwith two portions of ethyl acetate and was air-dried by blowing nitrogengas to remove the solvent. The resulting residue was treated with 1 mlof a 1:1 mixture of trifluoroacetic acid and dichloromethane containing10% triethylsilane by standing still for 1 hour. The reaction mixturewas air-dried by blowing nitrogen gas, and residue was dissolved in 0.5ml of N,N-dimethylformamide. Each of the solutions was separated andpurified by LC-MS by the procedure of Synthesis Process I-A, to give thefollowing compounds.

Example I-163N1-(3-Imidazo[1,2-a]pyridin-2-yl-1H-5-indazolyl)-2-(3-thienyl)acetamide

MS (ESI) m/z 374 MH⁺

Example I-164N2-(3-Imidazo[1,2-a]pyridin-2-yl-1H-5-indazolyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide

MS (ESI) m/z 408 MH⁺

Example I-165 Cyclopropanecarboxylic acid[3-(fluorobenzo[b]furan-2-yl)-1H-indazol-5-yl]amide

MS (ESI) m/z 336 MH⁺

Example I-166 5-Oxo-pyrrolidine-(2S)-2-carboxylic acid[3-(fluorobenzo[b]furan-2-yl)-1H-indazol-5-yl]amide

MS (ESI) m/z 379 MH⁺

The compounds according to Examples I-167 and I-168 were synthesized byfollowing Synthesis Process I-F.

Synthesis Process I-F

As a starting material, 0.19 g of tert-butyl3-(2-naphthyl)-5-(hydroxymethyl)-1H-1-indazolecarboxylate produced inProduction Example I-33 was subjected to the procedures of ProductionExample I-30a and I-30b, to give 0.15 g of tert-butyl5-(aminomethyl)-3-(2-naphthyl)-1H-1-indazolecarboxylate as a colorlessoil. The compound was allowed to react with any of carboxylic acids andwas then treated with an acid according to the procedure of SynthesisProcess I-E. Each of the reaction mixtures was separated and purified byLC-MS under the conditions of Synthesis Process I-A, to give thefollowing compounds.

Example I-167N1-{[3-(2-Naphthyl)-1H-5-indazolyl]methyl}-3-methoxypropanamide

MS (ESI) m/z 360 MH⁺

Example I-168N1-{[3-(2-Naphthyl)-1H-5-indazolyl]methyl}-2-(3-thienyl)acetamide

MS (ESI) m/z 398 MH⁺

The compound according to Examples I-169 to I-171 were synthesized byfollowing Synthesis Process I-G.

Synthesis Process I-G

To an ice-cold solution of 373 mg of tert-butyl5-(hydroxymethyl)-3-(2-naphthyl)-1H-1-indazolecarboxylate produced inProduction Example I-33 in 10 ml dry tetrahydrofuran were added dropwise0.17 ml of triethylamine and 0.09 ml of methanesulfonyl chloride, andthe mixture was stirred for 20 minutes. Each 1 ml of the reactionmixture was pipetted into test tubes, each of which was treated with 0.4ml of a 1 M solution of any of amines in dimethylformamide with stirringfor one day. The suspended reaction mixture was diluted with a smallamount of water and was filtrated through a membrane filter. Each of thereaction mixtures was separated and purified by LC-MS under theconditions of Synthesis Process I-A and thereby yielded the followingtest compounds.

Example I-169 4-{[3-(2-Naphthyl)-1H-5-indazolyl]methyl}morpholine

MS (ESI) m/z 344 MH⁺

Example I-1705-(2,3-Dihydro-1H-1-indolylmethyl)-3-(2-naphthyl)-1H-indazole

MS (ESI) m/z 376 MH⁺

Example I-1715-{[4-(2-Methoxyphenyl)piperazino]methyl}-3-(2-naphthyl)-1H-indazole

MS (ESI) m/z 449 MH⁺

The compound according to Examples I-172 and I-173 were syntheticallyprepared by following Synthesis Process I-H.

Synthesis Process I-H

Into test tubes were pipetted 15 mg of tert-butyl5-(hydroxymethyl)-3-(2-naphthyl)-1H-1-indazolecarboxylate produced inProduction Example I-33 and 0.5 ml of tetrahydrofuran, each of which wastreated with 1 equivalent of any of phenols. Each of the mixtures wasfurther treated with 15 mg of triphenylphosphine and 0.02 ml of a 40%solution of diethyl azodicarboxylate in toluene by standing still forone week. Each of the reaction mixtures was separated and purified byLC-MS under the conditions of Synthesis Process I-A, the solvent wasremoved by blowing nitrogen gas, and the residue was treated with 1 mlof a 1:1 mixture solution of trifluoroacetic acid and dichloromethanecontaining 10% triethylsilane by standing still for 1 hour. The solventin the reaction mixture was removed by blowing nitrogen gas, theresulting residue was dissolved in 0.5 ml of N,N-dimethylformamide, wasseparated and purified by LC-MS under the conditions of SynthesisProcess I-A and thereby yielded the following compounds.

Example I-172 5-[(3-Methoxyphenoxy)methyl]-3-(2-naphthyl)-1H-indazole

MS (ESI) m/z 381 MH⁺

Example I-173 7-[3-(2-Naphthyl)-1H-5-indazolyl]methoxy-2H-2-chromenone

MS (ESI) m/z 419 MH⁺

Production Example II-1-a 1-Bromo-4-fluoro-2-methoxy-benzene

A total of 10 g of 2-bromo-5-fluoro-phenol was dissolved in 105 ml ofN,N-dimethylformamide, 10.9 g of potassium carbonate and 4.9 ml ofiodomethane were added under ice-cooling, and the mixture was stirred atroom temperature for 3 hours. Water was added to the reaction mixture,followed by extracting with diethyl ether. The resulting organic layerwas washed with brine, dried over magnesium sulfate and the solvent wasevaporated, to give 9.75 g of the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.88 (3H, s), 6.59 (1H, td, J=8.4, 2.8 Hz),6.65 (1H, dd, J=10.4, 2.8 Hz), 7.47 (1H, dd, J=8.4, 6.0 Hz)

Production Example II-1-b(5-Bromo-2-fluoro-4-methoxy-phenyl)-(3-fluoro-phenyl)-methanone

A total of 716 mg of aluminium chloride was suspended in 24.4 ml ofdichloromethane and was then mixed with 0.65 ml of 3-fluorobenzoylchloride and 1 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained inProduction Example II-1-a under stirring at −60° C. The mixture wasraised in temperature to room temperature over 2.5 hours and was stirredfor further 3 hours. Water was added to the reaction mixture underice-cooling, followed by extracting with diethyl ether. The resultingorganic layer was washed with saturated aqueous sodium hydrogencarbonatesolution and brine, dried over magnesium sulfate and the solvent wasevaporated. The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:10), to give 856 mg of the titlecompound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ 3.98 (3H, s), 6.69 (1H, d, J=11.6 Hz),7.27-7.58 (4H, m), 7.83 (1H, d, J=7.2 Hz)

Production Example II-1-c4-Fluoro-5-(3-fluoro-benzoyl)-2-methoxy-benzonitrile

A total of 856 mg of(5-bromo-2-fluoro-4-methoxy-phenyl)-(3-fluoro-phenyl)-methanone obtainedin Production Example II-1-b was dissolved in 13.1 ml ofN,N-dimethylformamide, 185 mg of zinc cyanide, 13.6 mg oftris(dibenzylideneacetone)dipalladium and 17.4 mg of1,1′-bis(diphenylphosphino)ferrocene were added thereto, and the mixturewas stirred at 120° C. in an atmosphere of nitrogen gas for 7 hours.After cooling to room temperature, water was added to the reactionmixture and the mixture was extracted with diethyl ether. The resultingorganic layer was washed with brine, dried over magnesium sulfate andthe solvent was evaporated. The residue was purified and separated bysilica gel column chromatography (ethyl acetate:hexane=1:2), to give 203mg of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, CDCl₃) δ 4.03 (3H, s), 6.78 (1H, d, J=11.6 Hz),7.30-7.37 (1H, m), 7.42-7.56 (3H, m), 7.89 (1H, d, J=7.6 Hz)

Production Example II-1-d3-(3-Fluoro-phenyl)-6-methoxy-1H-indazole-5-carbonitrile

A total of 203 mg of4-fluoro-5-(3-fluoro-benzoyl)-2-methoxy-benzonitrile obtained inProduction Example II-1-c was dissolved in 3 ml of tetrahydrofuran and 3ml of methanol, 7.4 ml of hydrazine monohydrate was added at roomtemperature under stirring, and the mixture was stirred at roomtemperature for 14 hours. Then, water was added and the mixture wasextracted with ethyl acetate. The resulting organic layer was washedwith 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonatesolution and brine, dried over magnesium sulfate and the solvent wasevaporated. The resulting crystals were washed with diethyl ether, togive 172 mg of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, CD₃OD) δ 4.01 (3H, s), 7.14 (1H, s), 7.18 (1H, td,J=8.4, 2.8 Hz), 7.54 (1H, td, J=8.4, 6.0 Hz), 7.62-7.68 (1H, m), 7.76(1H, J=8.4 Hz), 8.37 (1H, s)

Production Example II-1-e3-(3-Fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid

A total of 172 mg of3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carbonitrile obtained inProduction Example II-1-d was dissolved in 2 ml of acetic acid, 0.7 mlof water and 0.5 ml of sulfuric acid, followed by stirring at 110° C.for 18 hours. After cooling to room temperature, water was added to thereaction mixture. The resulting crystals were washed with water, to give159 mg of the title compound as light pink crystals.

¹H-NMR (400 MHz, CD₃OD) δ 3.99 (3H, s), 7.12 (1H, s), 7.14-7.20 (1H, m),7.55 (1H, td, J=8.0, 6.0 Hz), 7.61-7.67 (1H, m), 7.76 (1H, d, J=8.0 Hz),8.53 (1H, s)

Production Example II-2-a(3-Bromo-6-fluoro-2-methoxy-phenyl)-(3-fluoro-phenyl)-methanol

A total of 1.64 ml of diisopropylamine was dissolved in 27 ml oftetrahydrofuran, 6.8 ml of a 1.57 M solution of n-butyllithium in hexanewas added at −50° C. under stirring, and the mixture was stirred at −30°C. for 30 minutes. After cooling to −60° C., 2 g of1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-awas added and the mixture was stirred at −60° C. for 1 hour. Then, 1.55ml of 3-fluoro-benzaldehyde was added, followed by stirring for 1 hour.Saturated aqueous ammonium chloride solution was added to the reactionmixture, and the mixture was extracted with diethyl ether. The resultingorganic layer was washed with brine, dried over magnesium sulfate andthe solvent was evaporated, to give 2.4 g of the title compound as ayellow-brown oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.52 (3H, s), 3.56 (1H, d, J=10.4 Hz), 6.16(1H, d, J=11.6 Hz), 6.86 (1H, t, J=8.8 Hz), 6.92-6.99 (1H, m), 7.07-7.16(2H, m), 7.30 (1H, td, J=8.0, 6.0 Hz), 7.51 (1H, dd, J=8.8, 6.0 Hz)

Production Example II-2-b(3-Bromo1-6-fluoro-2-methoxy-phenyl)-(3-fluoro-phenyl)-methanone

A total of 2.4 g of(3-bromo-6-fluoro-2-methoxy-phenyl)-(3-fluoro-phenyl)-methanol obtainedin Production Example II-2-a was dissolved in 24.3 ml ofdichloromethane. Under ice-cooling and stirring, 1.28 g of1-methylmorpholine-N-oxide, 3.65 g of powdery 4A molecular sieve and 128mg of tetrapropylammonium perruthenate were added, followed by stirringat room temperature for 3 hours. Isopropyl alcohol was added to thereaction mixture and then the mixture was filtered through Celite. Theresulting filtrate was evaporated, and the residue was purified andseparated by silica gel column chromatography (ethylacetate:hexane=1:8), to give 2.07 g of the title compound as a paleyellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.80 (3H, s), 6.86 (1H, dd, J=8.8, 8.0 Hz),7.29-7.36 (1H, m), 7.42-7.50 (1H, m), 7.54-7.61 (2H, m), 7.66 (1H, dd,J=8.8, 5.6 Hz)

Production Example II-2-c5-Bromo-3-(3-fluoro-phenyl)-4-methoxy-1H-indazole

A total of 0.703 g of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-d, except using0.959 g of(3-bromo1-6-fluoro-2-methoxy-phenyl)-(3-fluoro-phenyl)-methanoneobtained in Production Example II-2-b.

¹H-NMR (400 MHz, CDCl₃) δ 3.51 (3H, s), 7.10-7.17 (1H, m), 7.17 (1H, d,J=8.8 Hz), 7.45 (1H, td, J=8.0, 6.0 Hz), 7.56 (1H, d, J=8.8 Hz),7.69-7.75 (1H, m), 7.77 (1H, d, J=8.0 Hz)

Production Example II-2-d3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carboxylic acid

A total of 230 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1H-indazoleobtained in Production Example II-2-c was dissolved in 4.78 ml oftetrahydrofuran, and 0.99 ml of a 1.59 M solution of n-butyllithium inhexane was added under stirring at −78° C. After stirring at −78° C. for30 minutes, dry ice was added. After stirring at the same temperaturefor 10 minutes, saturated aqueous ammonium chloride solution was added.The mixture was extracted with ethyl acetate, and the resulting organiclayer was washed with brine, dried over magnesium sulfate and thesolvent was evaporated. The residue was purified and separated by silicagel column chromatography (ethyl acetate:hexane=1:1), to give 41.1 mg ofthe title compound.

¹H-NMR (400 MHz, CD₃OD) δ 3.55 (3H, s), 7.14-7.21 (1H, m), 7.36 (1H, d,J=8.8 Hz), 7.50 (1H, td, J=8.0, 6.0 Hz), 7.60-7.65 (1H, m), 7.72 (1H, d,J=8.0 Hz), 7.88 (1H, d, J=8.8 Hz)

Production Example II-3-a2,4-Difluoro-3-{(3-fluoro-phenyl)-hydroxymethyl}-benzonitrile

A total of 9.35 g of the title compound was obtained as a yellow oil bythe procedure of Production Example II-2-a, except from 5 g of2,4-difluoro-benzonitrile.

¹H-NMR (400 MHz, CDCl₃) δ 6.30 (1H, s), 6.98-7.18 (4H, m), 7.33 (1H, td,J=8.0, 6.0 Hz), 7.58-7.65 (1H, m)

Production Example II-3-b 2,4-Difluoro-3-(3-fluoro-benzoyl)-benzonitrile

A total of 6.29 g of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-2-b, except from 9.35g of 2,4-difluoro-3-{(3-fluoro-phenyl)-hydroxymethyl}-benzonitrileobtained in Production Example II-3-a.

¹H-NMR (400 MHz, CDCl₃) δ 7.19 (1H, t, J=8.0 Hz), 7.36-7.44 (1H, m),7.52 (1H, td, J=8.0, 6.0 Hz), 7.55-7.60 (2H, m), 7.78-7.86 (1H, m)

Production Example II-3-c4-Fluoro-3-{(3-fluoro-phenyl)-1H-indazole-5-carbonitrile

A total of 479 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-d, except from 952mg of 2,4-difluoro-3-{(3-fluoro-benzoyl)-benzonitrile obtained inProduction Example II-3-b.

¹H-NMR (400 MHz, CD₃OD) δ 7.17-7.23 (1H, m), 7.49-7.66 (4H, m),7.70-7.75 (1H, m)

Production Example II-3-d4-Fluoro-3-{(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid

A total of 246 mg of the title compound was obtained as pale graycrystals by the procedure of Production Example II-1-e, except from 220mg of 4-fluoro-3-{(3-fluoro-phenyl)-1H-indazole-5-carbonitrile obtainedin Production Example II-3-c.

¹H-NMR (400 MHz, CD₃OD) 7.14-7.21 (1H, m), 7.39 (1H, d, J=8.8 Hz), 7.51(1H, td, J=8.0, 6.0 Hz), 7.57-7.64 (1H, m), 7.68-7.73 (1H, m), 7.96 (1H,dd, J=8.8, 6.4 Hz)

Production Example II-4-a(5-Bromo-2-fluoro-4-methyl-phenyl)-(3-fluoro-phenyl)-methanol

A total of 11.6 g of the title compound was obtained as a pale yellowoil by the procedure of Production Example II-2-a, except from 5.98 g of2-bromo-5-fluoro-toluene.

¹H-NMR (400 MHz, CDCl₃) δ 2.36 (3H, s), 6.06 (1H, s), 6.93 (1H, d,J=11.2 Hz), 6.96-7.00 (1H, m), 7.08-7.18 (1H, m), 7.31 (1H, td, J=8.0,6.0 Hz), 7.63 (1H, d, J=7.2 Hz)

Production Example II-4-b(5-Bromo1-2-fluoro-4-methyl-phenyl)-(3-fluoro-phenyl)-methanone

A total of 6.63 g of the title compound was obtained as a yellow oil bythe procedure of Production Example II-2-b, except from 11.6 g of(5-bromo-2-fluoro-4-methyl-phenyl)-(3-fluoro-phenyl)-methanol obtainedin Production Example II-4-a.

¹H-NMR (400 MHz, CDCl₃) δ 2.48 (3H, s), 7.08 (1H, d, J=10.4 Hz),7.28-7.35 (1H, m), 7.46 (1H, td, J=8.0, 5.6 Hz), 7.49-7.60 (2H, m), 7.73(1H, d, J=6.4 Hz)

Production Example II-4-c5-Bromo-3-(3-fluoro-phenyl)-6-methyl-1H-indazole

A total of 1.57 g of the title compound was obtained as white crystalsby the procedure of Production Example II-1-d, except from 2.42 g of(5-bromo1-2-fluoro-4-methyl-phenyl)-(3-fluoro-phenyl)-methanone obtainedin Production Example II-4-b.

¹H-NMR (400 MHz, CDCl₃) δ 2.56 3H, s), 7.09-7.16 (1H, m), 7.40 (1H, s),7.49 (1H, td, J=8.0, 6.0 Hz), 7.62-7.68 (1H, m), 7.70-7.75 (1H, m), 8.21(1H, s), 10.10 (1H, brs)

Production Example II-4-d3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid

A total of 195 mg of the title compound was obtained as pale browncrystals by the procedure of Production Example II-2-d, except from 670mg of 5-bromo-3-(3-fluoro-phenyl)-6-methyl-1H-indazole obtained inProduction Example II-4-c.

¹H-NMR (400 MHz, CD₃OD) δ 2.71 (3H, s), 7.12-7.20 (1H, m), 7.41 (1H, s),7.50-7.81 (4H, m), 8.61 (1H, s)

Production Example II-5-a 1,5-Dibromo-2,4-difluorobenzene

A total of 1.6 g of 1-bromo-2,4-difluorobenzene was suspended in 8.29 mlof sulfuric acid, and 1.62 g of N-bromosuccinimide was added underice-cooling. After stirring at room temperature for 17 hours, thereaction mixture was poured onto ice-water and extracted with ethylacetate. The resulting organic layer was washed with saturated aqueoussodium hydrogencarbonate solution and brine, dried over magnesiumsulfate and the solvent was evaporated. The residue was purified andseparated by silica gel column chromatography (hexane), to give 2.18 gof the title compound as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 6.99 (1H, t, J=8.0 Hz), 7.77 (1H, t, J=6.8 Hz)

Production Example II-5-b(5-Bromo-2,4-difluoro-phenyl)-(3-fluoro-phenyl)-methanol

A total of 2.02 g of 1,5-dibromo-2,4-difluorobenzene obtained inProduction Example II-5-a was dissolved in 38 ml of diethyl ether, and4.9 ml of a 1.58 M solution of n-butyllithium in hexane was added understirring at −70° C. After stirring for 1 hour, 4.9 ml ofm-fluorobenzaldehyde was added and the mixture was stirred for 15minutes. Saturated aqueous ammonium chloride solution was added to thereaction mixture, followed by extracting with ethyl acetate. Theresulting organic layer was washed with brine, dried over magnesiumsulfate and the solvent was evaporated. The residue was purified andseparated by silica gel column chromatography (ethylacetate:hexane=1:10), to give 0.96 g of the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 6.07 (1H, d, J=3.2 Hz), 6.87 (1H, dd, J=9.6,8.4 Hz), 6.95-7.04 (1H, m), 7.07-7.18 (2H, m), 7.33 (1H, td, J=8.4, 6.0Hz), 7.73 (1H, t, J=8.0 Hz)

Production Example II-5-c(5-Bromo-2,4-difluoro-phenyl)-(3-fluoro-phenyl)-methanone

A total of 8.34 g of the title compound was obtained by the procedure ofProduction Example II-2-b, except from 17.0 g of(5-bromo-2,4-difluoro-phenyl)-(3-fluoro-phenyl)-methanol obtained inProduction Example II-5-b.

¹H-NMR (400 MHz, CDCl₃) δ 7.02 (1H, t, J=8.4 Hz), 7.30-7.64 (4H, m),7.82 (1H, t, J=7.6 Hz)

Production Example II-5-d 2,4-Difluoro-5-(3-fluoro-benzoyl)-benzonitrile

A total of 1.63 g of the title compound was obtained as yellow-browncrystals by the procedure of Production Example II-1-c, except from 4.03g of (5-bromo-2,4-difluoro-phenyl)-(3-fluoro-phenyl-methanone obtainedin Production Example II-5-c.

¹H-NMR (400 MHz, CDCl₃) δ 7.13 (1H, t, J=8.8 Hz), 7.34-7.56 (4H, m),7.93 (1H, t, J=7.2 Hz)

Production Example II-5-e6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carbonitrile

A total of 0.982 g of the title compound was obtained as pale yellowcrystals by the procedure of Production Example I-1-d, except from 1.63g of 2,4-difluoro-5-(3-fluoro-benzoyl)-benzonitrile obtained inProduction Example II-5-d.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.26-7.36 (1H, m), 7.50-7.63 (1H, m), 7.73(1H, d, J=10.0 Hz), 7.80-7.86 (1H, m), 7.91 (1H, d, J=8.0 Hz), 8.88 (1H,d, J=6.0 Hz)

Production Example II-5-f6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid

A total of 415 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-e, except from 653mg of 6-fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carbonitrile obtainedin Production Example II-5-e.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.27-7.35 (1H, m), 7.49 (1H, d, J=11.2 Hz),7.63 (1H, td, J=8.0, 6.0 Hz), 7.70-7.76 (1H, m), 7.82 (1H, d, J=8.0 Hz)

Production Example II-63-(3-Fluoro-phenyl)-6-hydroxy-1H-indazole-5-carboxylic acid

A total of 96.2 mg of3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid obtained inProduction Example II-1-e was dissolved in 3.36 ml of dichloromethane,4.0 ml of a 1.0 M solution of boron tribromide in dichloromethane wasadded under ice-cooling, and the mixture was stirred at room temperaturefor 1.5 hours. Water was added to the reaction mixture, followed byextracting with ethyl acetate. The resulting organic layer was washedbrine, dried over magnesium sulfate and the solvent was evaporated, togive 84.1 mg of the crude product of the title compound.

¹H-NMR (400 MHz, CD₃OD) δ 6.93 (1H, s), 7.13-7.23 (1H, m), 7.50-7.79(3H, m), 8.63 (1H, s)

Production Example II-7-a 2-Amino-4-fluoro-benzoic acid ethyl ester

A total of 10 g of 2-amino-4-fluoro-benzoic acid was dissolved in 129 mlof ethanol, 6.45 ml of sulfuric acid was added and the mixture washeated under reflux for 11 hours. After cooling to room temperature, thesolvent was evaporated to about half. Water was added and the mixturewas extracted with ethyl acetate. The resulting organic layer was washedwith saturated aqueous sodium hydrogencarbonate solution and brine,dried over magnesium sulfate and the solvent was evaporated. The residuewas purified and separated by silica gel column chromatography (ethylacetate:hexane=1:5), to give 7.57 g of the title compound as a paleyellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 1.38 (3H, t, J=6.8 Hz), 4.32 (2H, q, J=6.8Hz), 5.88 (2H, brs), 6.28-6.38 (2H, m), 7.88 (1H, dd, J=8.8, 6.8 Hz)

Production Example II-7-b 2-Acetylamino-4-fluoro-benzoic acid ethylester

A total of 3.84 g of 2-amino-4-fluoro-benzoic acid ethyl ester obtainedin Production Example II-7-a was dissolved in 50 ml of pyridine, 1.64 mlof acetyl chloride was added under ice-cooling, and the mixture wasstirred for 1 hours. The reaction mixture was diluted with water and wasextracted with diethyl ether. The resulting organic layer was washedwith 1 N hydrochloric acid and brine, dried over magnesium sulfate, andthen evaporated, to give 4.0 g of the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 1.41 (3H, t, J=6.8 Hz), 2.14 (3H, s), 4.38(2H, q, J=6.8 Hz), 6.73-6.81 (1H, m), 8.06 (1H, dd, J=8.8, 6.4 Hz), 8.53(1H, dd, J=12.0, 2.4 Hz), 11.3 (1H, brs)

Production Example II-7-c 2-Acetylamino-4-fluoro-5-iodo-benzoic acidethyl ester

A total of 3.12 g of silver sulfate was suspended in 45 ml of sulfuricacid, 5 ml of water was added, and the mixture was stirred at roomtemperature for 15 minutes. 1 ml of iodine monochloride was added,followed by stirring at room temperature for 1 hour. The mixture wasfiltered, and to 44 ml of the filtrate was added 2 g of2-acetylamino-4-fluoro-benzoic acid ethyl ester obtained in ProductionExample II-7-b under ice-cooling, and the mixture was stirred for 1hour. The reaction mixture was poured onto ice-water and was extractedwith ethyl acetate. The resulting organic layer was washed withsaturated aqueous sodium hydrogencarbonate solution and brine, driedover magnesium sulfate and the solvent was evaporated. The residue waspurified and separated by silica gel column chromatography (ethylacetate:hexane=1:5), to give 2.9 g of the title compound as whitecrystals.

¹H-NMR (400 MHz, CDCl₃) δ 1.43 (3H, t, J=6.8 Hz), 2.24 (3H, s), 4.39(2H, q, J=6.8 Hz), 8.41 (1H, d, J=7.2 Hz), 8.59 (1H, d, J=11.2 Hz

Production Example II-7-d2-Acetylamino-4-fluoro-5-(3-fluoro-benzoyl)-benzoic acid ethyl ester

A total of 812 mg of 2-acetylamino-4-fluoro-5-iodo-benzoic acid ethylester obtained in Production Example II-7-c was dissolved in 13.9 ml ofanisole, and 956 mg of potassium carbonate, 356 mg of3-fluorophenyl-boronic acid and 49 mg ofbis(triphenylphosphine)palladium dichloride were added. After replacingthe inside atmosphere of the reaction system with carbon monoxide gas,the mixture was stirred at 80° C. in an atmosphere of carbon monoxide(normal pressure) for 14 hours. After cooling to room temperature andreplacing the inside atmosphere of the reaction system with nitrogengas, water was added and the mixture was extracted with ethyl acetate.The resulting organic layer was washed with brine, dried over magnesiumsulfate and the solvent was evaporated. The residue was purified andseparated by silica gel column chromatography (ethylacetate:hexane=1:5), to give 234 mg of the title compound as pale yellowcrystals.

¹H-NMR (400 MHz, CDCl₃) δ 1.43 (3H, t, J=6.8 Hz), 2.27 (3H, s), 4.41(2H, q, J=6.8 Hz), 7.05-7.12 (1H, m), 7.20-7.46 (3H, m), 8.15 (1H, d,J=8.8 Hz), 8.64 (1H, d, J=13.6 Hz)

Production Example II-7-e6-Acetylamino-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid ethylester

A total of 160 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-d, except from 234mg of 2-acetylamino-4-fluoro-5-(3-fluoro-benzoyl)-benzoic acid ethylester obtained in Production Example II-7-d.

¹H-NMR (400 MHz, CDCl₃) δ 1.47 (3H, t, J=6.8 Hz), 2.32 (3H, s), 4.46(2H, q, J=6.8 Hz), 7.12-7.19 (1H, m), 7.51 (1H, td, J=8.0, 6.0 Hz),7.64-7.70 (1H, m), 7.75 (1H, d, J=8.0 Hz), 8.79 (1H, s), 8.99 (1H, s)

Production Example II-7-f6-Acetylamino-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid

A total of 160 mg of6-acetylamino-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid ethylester obtained in Production Example II-7-e was dissolved in 3 ml ofethanol and 1 ml of 5 N aqueous sodium hydroxide solution, and thesolution was stirred at 50° C. for 2 hours. After cooling to roomtemperature, 1 N hydrochloric acid was added and the mixture wasextracted with ethyl acetate. The resulting organic layer was washedwith brine, dried over magnesium sulfate and the solvent was evaporated,to give 155 mg of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, CD₃OD) δ 2.24 (3H, s), 7.14-7.21 (1H, m), 7.56 (1H, td,J=8.0, 6.0 Hz), 7.63-7.68 (1H, m), 7.77 (1H, d, J=8.0 Hz), 8.79-8.85(2H, m)

Production Example II-8-a4-Fluoro-3-[(3-fluorophenyl)-hydroxymethyl]-5-methoxybenzonitrile

To a solution of 15.0 g of 4-fluoro-3-methoxybenzonitrile and 21.8 ml ofN,N,N′,N′,N″-pentamethyldiethylenetriamine in 300 ml tetrahydrofuran wasadded 65.5 ml of a 1.59 M solution of n-butyllithium in hexane at −78°C. in an atmosphere of nitrogen gas, followed by stirring at the sametemperature for 1 hour. At the same temperature, 10.5 ml of3-fluorobenzaldehyde was added dropwise, followed by stirring at thesame temperature for 1 hour. Then, water was added and the mixture wasextracted with diethyl ether. The organic layer was washed withsaturated aqueous ammonium chloride solution and brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. The crudeproduct was purified and separated by silica gel column chromatography(ethyl acetate:n-hexane=1:10 to 1:3), to give 7.1 g of the titlecompound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 2.55 (1H, brs), 3.89 (3H, s), 6.13 (1H, s),6.98 (1H, dt, J=2.0, 8.0 Hz), 7.10 (1H, d, J=8.0 Hz), 7.12 (1H, dd,J=2.0, 8.0 Hz), 7.16 (1H, d, J=8.0 Hz), 7.31 (1H, dt, J=5.6, 8.0 Hz),7.50 (1H, dd, J=2.0, 5.6 Hz)

Production Example II-8-b4-Fluoro-3-(3-fluorobenzoyl)-5-methoxybenzonitrile

To a solution of 7.0 g of4-fluoro-3-[(3-fluorophenyl)-hydroxymethyl]-5-methoxybenzonitrile in 70ml toluene was added 11.1 g of activated manganese dioxide at roomtemperature. After stirring at 60° C. for one day, the manganese dioxidewas filtered off through Celite. The solvent was removed and the crudeproduct was purified and separated by silica gel column chromatography(ethyl acetate:n-hexane=1:3), to give 640 mg of the title compound ascolorless crystals.

¹H-NMR (400 MHz, CDCl₃) δ 3.99 (3H, s), 7.35 (1H, dt, J=1.2, 5.6 Hz),7.37 (1H, dd, J=2.0, 8.0 Hz), 7.42 (1H, dd, J=2.0, 5.6 Hz), 7.48 (1H,dt, J=5.6, 8.0 Hz), 7.51-7.58 (2H, m)

Production Example II-8-c3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carbonitrile

To a solution of 640 mg of4-fluoro-3-(3-fluorobenzoyl)-5-methoxybenzonitrile in 6 ml ethanol wasadded 3 ml of hydrazine monohydrate at room temperature, followed bystirring at 70° C. for one day. The reaction mixture was evaporated, andthe resulting crystals were collected by filtration. The crystals weresequentially washed with ethanol and diethyl ether, to give 590 mg ofthe title compound as colorless crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.03 (3H, s), 7.23-7.29 (1H, m), 7.25 (1H,d, J=1.2 Hz), 7.55 (1H, dt, J=6.4, 8.0 Hz), 7.78 (1H, ddd, J=1.2, 2.4,6.4 Hz), 7.88 (1H, dt, J=1.2, 8.0 Hz), 8.31 (1H, d, J=1.2 Hz

Production Example II-8-d3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid

To 450 mg of 3-(3-fluorophenyl)-7-methoxy-1H-indazole-5-carbonitrilewere sequentially added 6 ml of glacial acetic acid, 2 ml of water and 2ml of concentrated sulfuric acid, followed by stirring at 100° C. forone day. After standing to cool, water was added to the reaction mixtureand the resulting crystals were collected by filtration. The crystalswere sequentially washed with isopropanol and diethyl ether, to give 428mg of the title compound as colorless crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.03 (3H, s), 7.27 (1H, dt, J=2.4, 8.0 Hz),7.37 (1H, s), 7.60 (1H, dt, J=6.4, 8.0 Hz), 7.69 (1H, ddd, J=1.2, 2.4,6.4 Hz), 7.80 (1H, d, J=8.0 Hz), 8.24 (1H, s)

Production Example II-9-a(5-Bromo-2-fluoro-3-methylphenyl)-(3-fluorophenyl)methanol

In an atmosphere of nitrogen gas, 74.1 ml of a 1.57 M solution ofn-butyllithium in hexane was added to a solution of 16.3 ml ofN,N-diisopropylamine in 400 ml tetrahydrofuran at 0° C., and the mixturewas stirred at the same temperature for 30 minutes. After cooling to−78° C., a solution of 20.0 g of 5-bromo-2-fluorotoluene in 40 mltetrahydrofuran was added dropwise. After stirring at the sametemperature for 1 hour, 11.2 ml of 3-fluorobenzaldehyde was addeddropwise and the mixture was stirred at the same temperature for 3hours. The reaction mixture was neutralized with 1 N hydrochloric acidand diluted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous magnesium sulfate, and the solvent was evaporated.The crude product was purified and separated by silica gel columnchromatography (ethyl acetate:n-hexane=1:20), to give 20.6 g of thetitle compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 2.23 (3H, s), 2.34 (1H, d, J=4.0 Hz), 6.06(1H, d, J=4.0 Hz), 6.98 (1H, dt, J=2.4, 8.0 Hz), 7.12 (1H, d, J=8.0 Hz),7.17 (1H, d, J=8.0 Hz), 7.25 (1H, d, J=6.0 Hz), 7.31 (1H, dt, J=6.0, 8.0Hz), 7.50 (1H, dd, J=2.4, 6.0 Hz)

Production Example II-9-b5-Bromo-3-(3-fluorophenyl)-7-methyl-1H-indazole

To a solution of 20.0 g of(5-bromo-2-fluoro-3-methylphenyl)-(3-fluorophenyl)methanol in 200 mltoluene was added 16.7 g of activated manganese dioxide at roomtemperature. After stirring at 80° C. for 2 hours, the manganese dioxidewas filtered off through Celite. After removing the solvent bydistillation, to a solution of the residue in 100 ml of ethanol wasadded 15.5 ml of hydrazine monohydrate at room temperature and themixture was heated under reflux for one day. The reaction mixture wasevaporated and diluted with ethyl acetate. The organic layer wassequentially washed with saturated aqueous ammonium chloride solutionand brine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated. A solution of the residue in 20 ml pyridine was stirred in asealed tube at 200° C. for 10 hours. After cooling, the reaction mixturewas evaporated, the residue was dissolved in ethyl acetate and 5 Nhydrochloric acid, and the aqueous layer was extracted with ethylacetate. The collected organic layer was washed with brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. Theresulting crystals were washed with ethyl acetate, to give 11.3 g of thetitle compound as colorless crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 2.58 (3H, s), 7.15 (1H, ddd, J=0.8, 2.4, 8.0Hz), 7.33 (1H, dd, J=0.8, 1.6 Hz), 7.53 (1H, dt, J=6.0, 8.0 Hz), 7.61(1H, ddd, J=1.6, 2.4, 6.0 Hz), 7.72 (1H, ddd, J=0.8, 1.6, 8.0 Hz), 8.31(1H, dd, J=0.8, 1.6 Hz)

Production Example II-9-c5-Bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole

To a solution of 2.56 g of5-bromo-3-(3-fluorophenyl)-7-methyl-1H-indazole in 30 ml ofdimethylformamide was added 0.50 g of sodium hydride at roomtemperature, and the mixture was stirred at the same temperature for 15minutes. At the same temperature, 2.34 g of triphenylmethane chloridewas added and the mixture was stirred at the same temperature for oneday. Water was added to the reaction mixture and the mixture was dilutedwith ethyl acetate. The organic layer was sequentially washed withsaturated aqueous ammonium chloride solution and brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated. The crudeproduct was purified and separated by silica gel column chromatography(ethyl acetate:n-hexane=1:10) and the resulting crystals were washedwith diethyl ether, to give 1.94 g of the title compound as colorlesscrystals.

¹H-NMR (400 MHz, CDCl₃) δ 1.43 (3H, s), 7.01 (1H, ddd, J=0.8, 2.4, 8.0Hz), 7.08 (1H, dd, J=0.8, 1.6 Hz), 7.10-7.32 (15H, m), 7.37 (1H, dt,J=6.0, 8.0 Hz), 7.41 (1H, ddd, J=1.6, 2, 4, 6.0 Hz), 7.54 (1H, ddd,J=0.8, 1.6, 8.0 Hz), 8.07 (1H, dd, J=0.8, 1.6 Hz)

Production Example II-9-d3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carbonitrile

To a solution of 1.5 g of5-bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole in 15 mldimethylformamide were added 0.64 g of zinc cyanide and 0.32 g oftetrakis(triphenylphosphine)palladium(0) at room temperature, and themixture was stirred at 100° C. for one day. At the same temperature,0.32 g of tetrakis(triphenylphosphine)palladium(0) was added and themixture was stirred at 130° C. for one day. The reaction mixture wasdiluted with ethyl acetate, and the organic layer was sequentiallywashed with saturated aqueous ammonium chloride solution and brine,dried over anhydrous magnesium sulfate, and the solvent was evaporated.The crude product was purified and separated by silica gel columnchromatography (ethyl acetate:n-hexane=1:10 to 1:1) and the resultingcrystals were washed with diethyl ether, to give 431 mg of the titlecompound as colorless crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 2.57 (3H, s), 7.26 (1H, dd, J=2.4, 8.0 Hz),7.53 (1H, s), 7.56 (1H, dt, J=6.0, 8.0 Hz), 7.79 (1H, dt, J=2.4, 6.0Hz), 7.89 (1H, d, J=8.0 Hz), 8.55 (1H, s)

Production Example II-9-e3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid

To 430 mg of 3-(3-fluorophenyl)-7-methyl-1H-indazole-5-carbonitrile weresequentially added 6.0 ml of glacial acetic acid, 2.0 ml of water and2.0 ml of concentrated sulfuric acid, followed by stirring at 100° C.for one day. After standing to cool, the reaction mixture was dilutedwith 20 ml of water, and the resulting crystals were collected byfiltration. The crystals were sequentially washed with water and diethylether, to give 360 mg of the title compound as colorless crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 2.58 (3H, s), 7.27 (1H, dd, J=2.4, 8.0 Hz),7.61 (1H, q, J=8.0 Hz), 7.71 (1H, dd, J=2.4, 8.0 Hz), 7.76 (1H, s), 7.81(1H, d, J=8.0 Hz), 8.46 (1H, s)

Production Example II-10-a(3-Bromo-6-fluoro-2-methoxy-phenyl)-naphthalen-2-yl-methanol

In an atmosphere of nitrogen gas, 2.38 ml of a 2.66 M solution ofn-butyllithium in hexane was added to a solution of 0.64 g ofN,N-diisopropylamine in 9 ml tetrahydrofuran at −78° C. After stirringat the same temperature for 1 hour, 1.18 g of1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-awas added dropwise. After stirring at the same temperature for 1 hourand 20 minutes, a solution of 0.99 g of 2-naphthoaldehyde in 4 mltetrahydrofuran was added dropwise. After stirring at the sametemperature for 1 hour and 20 minutes, water was added under ice-coolingand the mixture was extracted with diethyl ether for two times. Theextract was sequentially washing with water and brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. The crudeproduct was purified and separated by silica gel column chromatography,to give 1.72 g of the title compound as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.46 (3H, s), 3.68 (1H, d, J=10.8 Hz), 6.35(1H, d, J=10.8 Hz), 6.88 (1H, t, J=8.8 Hz), 7.42-7.53 (4H, m), 7.80-7.85(4H, m)

Production Example II-10-b(3-Bromo-6-fluoro-2-methoxy-phenyl)-naphthalen-2-yl-methanone

To a solution of 1.72 g of(3-bromo-6-fluoro-2-methoxy-phenyl)-naphthalen-2-yl-methanol in 34.4 mlmethylene chloride was added 5.16 g of activated manganese dioxide,followed by stirring at room temperature for 17 hours. Then, themanganese dioxide was filtered off through Celite. The solvent wasremoved by distillation, to give 1.63 g of the title compound as ayellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.80 (3H, s), 6.91 (1H, dd, J=8.0, 8.8 Hz),7.51-7.55 (1H, m), 7.59-7.68 (2H, m), 7.87-7.93 (3H, m), 8.02 (1H, dd,J=1.6, 8.4 Hz), 8.20 (1H, bs)

Production Example II-10-c5-Bromo-4-methoxy-3-naphthalen-2-yl-1H-indazole

A total of 1.63 g of(3-bromo-6-fluoro-2-methoxy-phenyl)-naphthalen-2-yl-methanone wasdissolved in 15 ml of pyridine, 2.2 ml of hydrazine monohydrate wasadded, followed by stirring at 100° C. for 6 hours. Water was added tothe reaction mixture, and then it was extracted with ethyl acetate fortwo times. The organic layer was sequentially washed with 1 Nhydrochloric acid, water, saturated aqueous sodium hydrogencarbonatesolution and brine, dried over anhydrous magnesium sulfate and thesolvent was removed by distillation. Then, the resulting crystals werewashed with hexane once and dried in vacuo, to give 0.923 g of the titlecompound as brown crystals.

¹H-NMR (400 MHz, CD₃OD) δ 3.39 (3H, s), 7.31 (1H, d, J=8.8 Hz),7.52-7.58 (3H, m), 7.91-8.03 (4H, m), 8.40 (1H, bs)

ESI-MS: m/z=351, 353 (M−H)⁻

Production Example II-10-d4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid

In an atmosphere of nitrogen gas, 2.94 ml of a 2.66 M solution ofn-butyllithium in hexane was added to a solution of 0.923 g of5-bromo-4-methoxy-3-naphthalen-2-yl-1H-indazole in 26 ml tetrahydrofuranat −78° C. After stirring at the same temperature for 1 hour and 15minutes, carbon dioxide gas was bubbled into the reaction mixture at thesame temperature for 10 minutes. After stirring at the same temperaturefor further 15 minutes, the mixture was stirred at room temperature for20 minutes. Saturated aqueous ammonium chloride solution was added andthe mixture was extracted ethyl acetate for two times. The organic layerwas washed with brine once, dried over anhydrous magnesium sulfate andthe solvent was evaporated. The resulting crystals were washed with oneportion of a 1:1 solvent of hexane:diethyl ether, and dried in vacuo, togive 0.586 g of the title compound as brown crystals.

¹H-NMR (400 MHz, CD₃OD) δ 3.48 (3H, s), 7.36 (1H, d, J=8.8 Hz),7.51-7.55 (2H, m), 7.88-8.02 (5H, m), 8.39 (1H, bs)

ESI-MS: m/z=317 (M−H)⁻

Production Example II-11-a 3-Bromo-6-fluoro-2-methoxy-benzaldehyde

In an atmosphere of nitrogen gas, 18.7 ml of a 2.66 M solution ofn-butyllithium in hexane was added to a solution of 5 g ofN,N-diisopropylamine in 89 ml tetrahydrofuran at −78° C. After stirringat the same temperature for 1 hour and 10 minutes, 9.27 g of1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-awas added dropwise. After stirring at the same temperature for 1.5hours, 5.52 ml of N-formylpiperidine was added dropwise. After stirringat the same temperature for 25 minutes, 9 ml of acetic acid was added atthe same temperature, water was added at room temperature, and themixture was extracted with diethyl ether for three times. The extractwas sequentially washed with 0.2 N hydrochloric acid, water and brine,dried over anhydrous magnesium sulfate and the solvent was evaporated.The crude product was purified and separated by silica gel columnchromatography, to give 5.65 g of the title compound as pale yellowcrystals.

¹H-NMR (400 MHz, CDCl₃) δ 3.97 (3H, s), 6.90 (1H, dd, J=9.0, 9.6 Hz),7.76 (1H, dd, J=5.6, 9.0 Hz), 10.35 (1H, s)

Production Example II-11-bBenzo[b]furan-2-yl-(3-bromo-6-fluoro-2-methoxy-phenyl)-methanol

In an atmosphere of nitrogen gas, 3.56 ml of a 2.66 M solution ofn-butyllithium in hexane was added to a solution of 1.12 g of2,3-benzofuran in 10 ml tetrahydrofuran at −78° C. After stirring at thesame temperature for 10 minutes, the mixture was stirred underice-cooling for 15 minutes and was then stirred at −78° C. for 8minutes. Then, a solution of 2 g of3-bromo-6-fluoro-2-methoxy-benzaldehyde in 3.5 ml tetrahydrofuran wasadded dropwise at the same temperature. After stirring at the sametemperature for 30 minutes, saturated aqueous ammonium chloride solutionwas added at the same temperature. Water was added at room temperatureand the mixture was extracted with diethyl ether for two times. Theorganic layer was sequentially washed with water and brine, dried overanhydrous magnesium sulfate and the solvent was evaporated. The crudeproduct was purified and separated by silica gel column chromatography,to give 2 g of the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.74-3.78 (4H, m), 6.28 (1H, d, J=10.4 Hz),6.647-6.652 (1H, m), 6.86 (1H, t, J=9.2 Hz), 7.18-7.26 (2H, m),7.40-7.43 (1H, m), 7.51-7.54 (2H, m)

Production Example II-11-cBenzo[b]furan-2-yl-(3-bromo-6-fluoro-2-methoxy-phenyl)-methanone

A total of 1.93 g of the title compound was obtained as a yellow oil bythe procedure of Production Example II-10-b, except from 2 g ofbenzo[b]furan-2-yl-(3-bromo-6-fluoro-2-methoxy-phenyl)-methanol.

¹H-NMR (400 MHz, CDCl₃) δ 3.86 (3H, s), 6.90 (1H, dd, J=8.0, 8.8 Hz),7.29-7.33 (1H, m), 7.37 (1H, bs), 7.48-7.53 (1H, m), 7.58-7.61 (1H, m),7.64-7.69 (2H, m)

Production Example II-11-d3-Benzo[b]furan-2-yl-5-bromo-4-methoxy-1H-indazole

A total of 1.38 g of the title compound was obtained as brown crystalsby the procedure of Production Example II-10-c, except from 1.93 g ofbenzo[b]furan-2-yl-(3-bromo-6-fluoro-2-methoxy-phenyl)-methanone.

¹H-NMR (400 MHz, CD₃OD) δ 3.86 (3H, s), 7.25-7.37 (3H, m), 7.53 (1H, d,J=1.2 Hz), 7.57-7.61 (2H, m), 7.69-7.71 (1H, m)

ESI-MS: m/z=341, 343 (M−H)⁻

Production Example II-11-e3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylic acid

A total of 0.2 g of the title compound was obtained as brown crystals bythe procedure of Production Example II-10-d, except from 0.69 g of3-benzo[b]furan-2-yl-5-bromo-4-methoxy-1H-indazole.

¹H-NMR (400 MHz, CD₃OD) δ 3.48 (3H, s), 7.36 (1H, d, J=8.8 Hz),7.51-7.55 (2H, m), 7.88-8.02 (5H, m), 8.39 (1H, bs ESI-MS: m/z=307(M−H).

Production Example II-12-aBenzo[b]thiophen-2-yl-(3-bromo-6-fluoro-2-methoxy-phenyl)-methanol

A total of 2.14 g of the title compound was obtained as an orange oil bythe procedure of Production Example II-11-b, except from 2 g of3-bromo-6-fluoro-2-methoxy-benzaldehyde obtained in Production ExampleII-11-a and benzo[b]thiophene.

¹H-NMR (400 MHz, CDCl₃) δ 3.66 (3H, s), 4.05 (1H, d, J=11.2 Hz), 6.38(1H, d, J=11.2 Hz), 6.88 (1H, t, J=9.2 Hz), 6.97-6.98 (1H, m), 7.26-7.33(2H, m), 7.54 (1H, dd, J=6.0, 8.8 Hz), 7.64-7.66 (1H, m), 7.77-7.79 (1H,m)

Production Example II-12-bBenzo[b]thiophen-2-yl-(3-bromo-6-fluoro-2-methoxy-phenyl)-methanone

A total of 2.04 g of the title compound was obtained as an orange oil bythe procedure of Production Example II-10-b, except from 2.14 g ofbenzo[b]thiophen-2-yl-(3-bromo-6-fluoro-2-methoxy-phenyl)-methanol.

¹H-NMR (400 MHz, CDCl₃) δ 3.85 (3H, s), 6.91 (1H, dd, J=7.6, 8.8 Hz),7.37-7.41 (1H, m), 7.46-7.50 (1H, m), 7.64-7.68 (2H, m), 7.81-7.84 (1H,m), 7.88-7.90 (1H, m)

Production Example II-12-c3-Benzo[b]thiophen-2-yl-5-bromo-4-methoxy-1H-indazole

A total of 1.42 g of the title compound was obtained as black-greencrystals by the procedure of Production Example II-10-c, except from2.04 g ofbenzo[b]thiophen-2-yl-(3-bromo-6-fluoro-2-methoxy-phenyl)-methanone.

¹H-NMR (400 MHz, CD₃OD) δ 3.76 (3H, s), 7.29 (1H, d, J=8.8 Hz),7.33-7.39 (2H, m), 7.58 (1H, d, J=8.8 Hz), 7.86-7.88 (2H, m), 8.10 (1H,bs)

ESI-MS: m/z=357, 359 (M−H)⁻

Production Example II-12-d3-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid

A total of 0.64 g of the title compound was obtained as black-greencrystals by the procedure of Production Example II-10-d, except from1.42 g of 3-benzo[b]thiophen-2-yl-5-bromo-4-methoxy-1H-indazole.

¹H-NMR (400 MHz, CD₃OD) δ 3.84 (3H, s), 7.33-7.39 (3H, m), 7.86-7.90(3H, m), 8.14 (1H, bs)

ESI-MS: m/z=323 (M−H)⁻

Production Example II-13-a 2,4-Difluoro-3-formyl-benzonitrile

In an atmosphere of nitrogen gas, 66 ml of a 1.6 M solution ofn-butyllithium in hexane was added to an ice-cold solution of 11.1 g ofN,N-diisopropylamine in 100 ml tetrahydrofuran, and the mixture wasstirred at the same temperature for 20 minutes. After cooling to −78°C., a solution of 13.9 g of 2,4-difluorobenzonitrile in 15 mltetrahydrofuran was added dropwise. After stirring at the sametemperature for 10 minutes, 8.6 ml of dimethylformamide was addeddropwise and the mixture was stirred at the same temperature for 15minutes. After adding 20 ml of glacial acetic acid to the reactionmixture, 200 ml of water was added and the mixture was extracted withdiethyl ether for two times. The organic layer was sequentially washedwith 0.2 N hydrochloric acid and brine, dried over anhydrous magnesiumsulfate and the solvent was evaporated. The resulting crude crystalswere triturated with diethyl ether-n-hexane, to give 8.61 g of the titlecompound as bright yellow crystals.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.53 (1H, t, J=8.8 Hz), 8.33 (1H, ddd,J=6.0, 7.2, 8.8 Hz), 10.17 (1H, s)

Production Example II-13-b 4-Fluoro-1H-indazole-5-carbonitrile

A total of 8.55 g of 2,4-difluoro-3-formyl-benzonitrile obtained inProduction Example II-13-a was dissolved in 40 ml of tetrahydrofuran and40 ml of methanol, and 5.1 ml of hydrazine monohydrate was added,followed by stirring at room temperature for three days and was furtherstirred at 50° C. for 3 hours and at 70° C. for 3 hours. The reactionmixture was added with 150 ml of ice-water, 300 ml of ethyl acetate and100 ml of tetrahydrofuran were added, and unnecessary matters werefiltered off. The organic layer was sequentially washed with water andbrine, dried over anhydrous magnesium sulfate and the solvent wasevaporated. The crude product was purified and separated by silica gelcolumn chromatography (ethyl acetate:toluene=1:9 to 1:4), to give 509 mgof the title compound as bright yellow crystals. In addition, a portionwith impurities was purified again by silica gel column chromatography(ethyl acetate:n-hexane=1:4 to 1:0), to give 1.80 g of the titlecompound as bright yellow crystals.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.58 (1H, d, J=8.8 Hz), 7.70 (1H, dd, J=6.0,8.8 Hz), 8.45 (1H, s), 13.94 (1H, s)

Production Example II-13-c 4-Fluoro-1H-indazolecarboxylic acid methylester

To 1.65 g of 4-fluoro-1H-indazole-5-carbonitrile obtained in ProductionExample II-13-b were added 8 ml of glacial acetic acid, 8 ml of waterand 16 ml of concentrated sulfuric acid, and the mixture was stirred at110° C. for 4 hours. After standing to cool, 150 mg of ice-water wasadded, and the precipitated carboxylic acid was collected by filtration.Under ice-cooling, to a solution of the resulting carboxylic acid in 12ml dimethylformamide and 40 ml tetrahydrofuran was added an excessamount of a solution of diazomethane in diethyl ether, and the mixturewas stirred at the same temperature for 45 minutes. The solvent wasevaporated, and the residue was dissolved in 100 ml of ethyl acetate.The mixture was sequentially washed with saturated aqueous sodiumhydrogencarbonate solution, water and brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated, to give 1.98 g of thetitle compound as bright yellow crystals.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.87 (3H, s), 7.45 (1H, d, J=8.8 Hz), 7.82(1H, dd, J=6.8, 8.8 Hz), 8.36 (1H, s), 13.70 (1H, s)

Production Example II-13-d 3-Bromo-4-fluoro-1H-5-indazolecarboxylic acidmethyl ester

To a solution of 2.2 g of 4-fluoro-1H-5-indazolecarboxylic acid methylester obtained in Production Example II-13-c in 20 ml dimethylformamidewas added 2.12 g of N-bromosuccinimide at room temperature, and themixture was stirred at the same temperature for 1 hour. After removingthe solvent by distillation, 120 ml of ethyl acetate was added to theresidue. The mixture was sequentially washed with half-saturated aqueoussodium hydrogencarbonate solution, water and brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated, to give 3.0 g of thetitle compound as bright yellow crystals.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.88 (3H, s), 7.48 (1H, d, J=8.8 Hz), 7.85(1H, dd, J=6.4, 8.8 Hz), 14.00 (1H, s)

Production Example II-13-e3-Bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl ester

Under ice-cooling, to a solution of 2.99 g of3-bromo-4-fluoro-1H-5-indazolecarboxylic acid methyl ester obtained inProduction Example II-13-d in 30 ml tetrahydrofuran was added 526 mg of60% sodium hydride, and the mixture was stirred for 25 minutes. Then,3.21 g of triphenylmethyl chloride was added and the mixture was stirredat the same temperature for 15 minutes and further stirred at roomtemperature for 45 minutes. The reaction mixture was ice-cooled again,saturated aqueous sodium hydrogencarbonate solution was added and themixture was extracted with 100 ml of ethyl acetate. The organic layerwas sequentially washed with water (×2) and brine, dried over anhydrousmagnesium sulfate and the solvent was evaporated. The crude product waspurified and separated by silica gel column chromatography (ethylacetate:hexane=1:9), and the resulting crystals were recrystallized fromdiisopropyl ether, to give 1.73 g of the title compound as whiteneedles.

¹H-NMR (400 MHz, DMSO-d₆) δ 3.83 (3H, s), 6.30 (1H, d, J=8.8 Hz),7.12-7.20 (6H, m), 7.30-7.40 (9H, m), 7.55 (1H, dd, J=6.8, 8.8 Hz)

Production Example II-13-f3-Benzo[b]thiophen-2-yl-4-fluoro-1H-5-indazolecarboxylic acid methylester

To a solution of 515 mg of3-bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl esterobtained in Production Example II-13-e in 7.5 ml dimethylformamide weresequentially added 267 mg of 2-benzo[b]thiopheneboronic acid, 1 ml of anaqueous solution of 291 mg of potassium fluoride, 30 mg of2-(di-tert-butylphosphino)biphenyl and 12 mg of palladium(II) acetate,and the mixture was stirred at 55° C. for 1 hour. The reaction mixturewas ice-cooled, and then the precipitated crystals were collected byfiltration. The resulting crystals were dissolved in a mixture solutionof ethyl acetate and tetrahydrofuran, and the mixture was sequentiallywashed with water, half-saturated aqueous sodium hydrogencarbonatesolution and brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated, to give 504 mg of a crude coupling product. Atotal of 350 mg of the resulting crude coupling product was suspended in4 ml of methylene chloride, 2 ml of trifluoroacetic acid and 0.1 ml oftriisopropylsilane were added, and the mixture was stirred at roomtemperature for 15 minutes. To the reaction mixture was added saturatedaqueous sodium hydrogencarbonate solution and it was extracted with 50ml of ethyl acetate. The organic layer was sequentially washed withsaturated aqueous sodium hydrogencarbonate solution and brine, driedover anhydrous magnesium sulfate and the solvent was evaporated. Thecrude product was purified and separated by silica gel columnchromatography (ethyl acetate:toluene=1:9), to give 154 mg of the titlecompound as pale yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.91 (3H, s), 7.38-7.45 (2H, m), 7.52 (1H,d, J=8.8 Hz), 7.91 (1H, dd, J=6.8, 8.8 Hz), 7.96-8.03 (2H, m), 8.05 (1H,s), 14.01 (1H, s).

Production Example II-13-g3-Benzo[b]thiophen-2-yl-4-fluoro-1H-5-indazolecarboxylic acid

To a solution of 152 mg of3-benzo[b]thiophen-2-yl-4-fluoro-1H-5-indazolecarboxylic acid methylester obtained in Production Example II-13-f in a mixture of 2 ml oftetrahydrofuran and 2 ml of methanol was added 1 ml of 5 N aqueoussodium hydroxide solution, and the mixture was stirred at 55° C. for 2.5hours. After standing to cool, 5.5 ml of 1 N hydrochloric acid was addedand the mixture was extracted with ethyl acetate. The organic layer wassequentially washed with water and brine, dried over anhydrous magnesiumsulfate and the solvent was evaporated. The crude product wasrecrystallized from tetrahydrofuran-ethyl acetate, to give 104 mg of thetitle compound as pale red crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.36-7.43 (2H, m), 7.47 (1H, d, J=8.8 Hz),7.88 (1H, dd, J=6.4, 8.8 Hz), 7.95-8.00 (2H, m), 8.03 (1H, s), 13.16(1H, s).

Production Example II-14-a4-Fluoro-3-naphthalen-2-yl-1H-5-indazolecarboxylic acid methyl ester

By the procedure of Production Example II-13-f, 495 mg of a Suzukicoupling product was obtained from 515 mg of3-bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl esterobtained in Production Example II-13-e and 258 mg ofn-naphthaleneboronic acid. A total of 350 mg of the coupling product wassubjected to deprotection (on trityl group) by the procedure ofProduction Example II-13-f, to give 154 mg of the title compound asbright yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.88 (3H, s), 7.52 (1H, d, J=8.8 Hz),7.56-7.62 (2H, m), 7.89 (1H, dd, J=6.4, 8.0 Hz), 7.96-8.10 (4H, m) 8.39(1H, s), 13.94 (1H, s)

Production Example II-14-b4-Fluoro-3-naphthalen-2-yl-1H-5-indazolecarboxylic acid

A total of 63 mg of the title compound was obtained as bright yellowcrystals by the procedure of Production Example II-13-g, except using152 mg of 4-fluoro-3-naphthalen-2-yl-1H-5-indazolecarboxylic acid methylester produced in Production Example II-14-a.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.49 (1H, d, J=8.8 Hz), 7.55-7.61 (2H, m),7.88 (1H, dd, J=6.4, 8.8 Hz), 7.96-8.08 (4H, m), 8.39 (1H, s), 13.08(1H, s), 13.88 (1H, s).

Production Example II-15-a 3-Benzo[b]furan-2-yl-1H-5-indazolecarboxylicacid methyl ester

A total of 123 mg of the title compound was obtained as bright yellowcrystals by the procedure of Production Example II-13-f, except from 308mg of 3-bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic acid methylester produced in Production Example II-13-e and 145 mg of2-benzo[b]furanboronic acid.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.91 (3H, s), 7.32 (1H, t, J=7.6 Hz), 7.39(1H, dd, J=7.6, 8.4 Hz), 7.51 (1H, s), 7.54 (1H, d, J=8.8 Hz), 7.69 (1H,d, J=8.4 Hz), 7.78 (1H, d, J=7.6 Hz), 7.91 (1H, dd, J=6.4, 8.8 Hz),14.15 (1H, s)

Production Example II-15-b 3-Benzo[b]furan-2-yl-1H-5-indazolecarboxylicacid

A total of 115 mg of the title compound was obtained as bright yellowcrystals by the procedure of Production Example II-13-f, except from 121mg of 3-benzo[b]furan-2-yl-1H-5-indazolecarboxylic acid methyl esterobtained in Production Example II-15-a.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.32 (1H, t, J=7.6 Hz), 7.39 (1H, dd, J=7.6,8.0 Hz), 7.50 (1H, s), 7.50 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=8.0 Hz),7.76 (1H, d, J=7.6 Hz), 7.90 (1H, dd, J=6.8, 8.8 Hz), 13.18 (1H, s),14.09 (1H, s)

Production Example II-16-aBenzo[b]thiophen-2-yl-(5-bromo-2,4-difluorophenyl)methanone

As a raw material, 17.7 g of 1,5-dibromo-2,4-difluorobenzene obtained inProduction Example II-5-a was subjected to lithiation withn-butyllithium by the procedure of Production Example II-5-b, wassubjected to formylation with N,N-dimethylformamide, to give 10.7 g of5-bromo-2,4-difluorobenzaldehyde. This compound was allowed to reactwith benzothiophene by the procedure of Production Example II-12-a toyield an alcohol, and then the alcohol was oxidized by the procedure ofProduction Example II-10-b, to give 9.7 g of the title compound as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 7.07 (1H, t, J=8.6 Hz), 7.44 (1H, t, J=8.4Hz), 7.52 (1H, t, J=8.4 Hz), 7.77 (1H, s), 8.65 (1H, d, J=6.6 Hz),13.50-13.60 (1H, bs).

Production Example II-16-b5-(Benzo[b]thiophen-2-carbonyl)-2,4-difluoro-benzonitrile

A total of 1.46 g of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-c, except from 2.98g of benzo[b]thiophen-2-yl-(5-bromo-2,4-difluorophenyl)methanone.

¹H-NMR (400 MHz, CDCl₃) δ 7.16 (1H, t, J=8.8 Hz), 7.44 (1H, t, J=8.0Hz), 7.53 (1H, t, J=8.0 Hz), 7.73 (1H, s), 7.88 (1H, d, J=8.0 Hz), 7.91(1H, d, J=8.0 Hz).

Production Example II-16-c3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carbonitrile

A total of 1.08 g of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-10-c, except from1.46 g of 5-(benzo[b]thiophen-2-carbonyl)-2,4-difluoro-benzonitrile.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.37-7.45 (2H, m), 7.74 (1H, d, J=10.0 Hz),7.86-7.91 (1H, m), 7.97-8.01 (1H, m), 8.39 (1H, s), 9.06 (1H, d, J=6.0Hz).

Production Example II-16-d3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carboxylic acid

A total of 600 mg of3-benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carbonitrile obtained inProduction Example II-16-c was hydrolyzed by the procedure of ProductionExample II-1-e, to give 310 mg of the title compound as a light brownpowder.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.36-7.43 (2H, m), 7.50 (1H, d, J=10.9 Hz),7.97-8.02 (2H, m), 8.16 (1H, s), 8.73 (1H, d, J=6.9 Hz), 13.15-13.30(1H, bs), 13.69 (1H, s).

Production Example II-17-a(5-Bromo-2,4-difluorophenyl)naphthalene-2-yl-methanone

A total of 13.6 g of 1,5-dibromo-2,4-difluorobenzene obtained inProduction Example II-5-a as a raw material was subjected to lithiationwith n-butyllithium by the procedure of Production Example II-5-b. Thiscompound was treated with 2-naphthoaldehyde to yield an alcohol, thealcohol was oxidized by the procedure of Production Example II-10-b, togive 13.5 g of the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 7.51-7.59 (2H, m), 7.63 (1H, d, J=9.0 Hz),7.93-7.96 (1H, m), 8.02 (1H, d, J=8.4 Hz), 8.14-8.18 (1H, m), 8.15 (1H,dd, J=1.6, 8.4 Hz), 8.56 (1H, d, J=1.6 Hz), 8.61 (1H, d, J=6.5 Hz),13.45-13.65 (1H, bs).

Production Example II-17-b2,4-Difluoro-5-(naphthalene-2-carbonyl)-benzonitrile

A total of 2.3 g of the title compound was obtained as a colorlesspowder by the procedure of Production Example II-1-c, except from 3.76 gof (5-bromo-2,4-difluorophenyl)naphthalene-2-yl-methanone.

¹H-NMR (400 MHz, CDCl₃) δ 7.15 (1H, t, J=8.8 Hz), 7.60 (1H, t, J=7.8Hz), 7.67 (1H, t, J=7.8 Hz), 7.91-7.97 (4H, m), 7.97 (1H, t, J=7.0 Hz),8.19 (1H, s).

Production Example II-17-c6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carbonitrile

A total of 2.1 g of 2,4-difluoro-5-(naphthalene-2-carbonyl)-benzonitrilewas allowed to react with hydrazine monohydrate by the procedure ofProduction Example II-10-c and thereby yielded 1.6 g of the titlecompound as a colorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.53-7.61 (2H, m), 7.72 (1H, d, J=9.6 Hz),7.93-7.98 (1H, m), 8.03 (1H, d, J=8.5 Hz), 8.14-8.19 (1H, m), 8.18 (1H,d, J=8.5 Hz), 8.65 (1H, s), 9.03 (1H, d, J=6.0 Hz), 13.83-13.97 (1H, bs)

Production Example II-17-d6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid

A total of 700 mg of6-fluoro-3-naphthalen-2-yl-1H-indazole-5-carbonitrile obtained inProduction Example II-17-c was hydrolyzed by the procedure of ProductionExample II-1-e and thereby yielded 610 mg of the title compound as acolorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.47 (1H, d, J=11.3 Hz), 7.53-7.60 (2H, m),7.94-7.99 (1H, m), 8.07 (1H, d, J=8.6 Hz), 8.09-8.14 (1H, m), 8.11 (1H,d, J=8.6 Hz), 8.50 (1H, s), 8.67 (1H, d, J=7.2 Hz), 13.05-13.25 (1H,bs), 13.62 (1H, s).

Production Example II-18-a5-Bromo-3-(3-fluoro-phenyl)-4-methoxy-1-trityl-1H-indazole

A total of 530 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1H-indazoleobtained in Production Example II-2-c was dissolved in 8.3 ml ofdimethylformamide, and 99 mg of sodium hydride (60% content) was addedunder ice-cooling and stirring. After stirring for 15 minutes, 483 mg oftriphenylmethyl chloride was added. After stirring at room temperaturefor 1 hour, saturated aqueous ammonium chloride solution was added andthe mixture was extracted with ethyl acetate. The resulting organiclayer was washed with brine, dried over magnesium sulfate and thesolvent was evaporated.

The crude product was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:8), to give 998 mg of the titlecompound as pale yellow crystals.

¹H-NMR (400 MHz, CDCl₃) δ 3.54 (3H, s), 6.16 (1H, d, J=8.8 Hz),7.01-7.08 (1H, m), 7.11 (1H, d, J=8.8 Hz), 7.16-7.40 (16H, m), 7.64-7.69(1H, m), 7.74 (1H, d, J=8.0 Hz).

Production Example II-18-b3-(3-Fluoro-phenyl)-4-methoxy-1-trityl-1H-indazol-5-ylamine

A total of 810 mg of5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1-trityl-1H-indazole obtained inProduction Example II-18-a was dissolved in 7.2 ml of toluene, 194 mg ofsodium t-butoxide, 0.29 ml of benzophenoneimine, 135 mg of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 74.5 mg oftris(dibenzylideneacetone)bispalladium were added, and the mixture wasstirred at 80° C. in an atmosphere of nitrogen gas for 8 hours. Thereaction mixture was cooled to room temperature, and diethyl ether wasadded. The mixture was filtrated through Celite, and the filtrate wasevaporated. The resulting residue was dissolved in 7.2 ml oftetrahydrofuran and 0.36 ml of 2 N hydrochloric acid was added, followedby stirring at room temperature for 3 hours. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture and themixture was extracted with diethyl ether. The resulting organic layerwas washed with brine, dried over magnesium sulfate and the solvent wasevaporated. The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:3), to give 426 mg of the titlecompound as reddish brown crystals.

¹H-NMR (400 MHz, CDCl₃) δ 3.46 (3H, s), 6.11 (1H, d, J=8.8 Hz), 6.55(1H, d, J=8.8 Hz), 6.96-7.04 (1H, m), 7.20-7.62 (16H, m), 7.68-7.74 (1H,m), 7.76 (1H, d, J=8.0 Hz).

Production Example II-19-a4-Fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazole-5-carboxylic acid

A total of 1.29 g of the title compound was obtained as an ocher yellowamorphous substance by the procedure of Production Example II-18-a,except from 1.25 g of4-fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid obtained inProduction Example II-3-d.

¹H-NMR (400 MHz, CD₃OD) δ 6.34 (1H, d, J=9.2 Hz), 7.08-7.16 (1H, m),7.16-7.37 (16H, m), 7.38-7.67 (3H, m).

Production Example II-19-b{4-Fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl}-carbamic acidbenzyl ester

A total of 1.29 g of4-fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazole-5-carboxylic acidobtained in Production Example II-19-a was dissolved in 12.5 ml oftoluene. Under stirring at room temperature, 0.38 ml of triethylamineand 0.566 ml of diphenylphosphoryl azide were added, and the mixture wasstirred at room temperature for 2 hours and at 120° C. for further 1.5hours. To the reaction mixture was added 0.776 ml of benzyl alcohol,followed by stirring at 120° C. for 1.5 hours. After cooling to roomtemperature, the reaction mixture was added with water, and extractedwith ethyl acetate. The resulting organic layer was washed with brine,dried over magnesium sulfate and the solvent was evaporated. The residuewas purified and separated by silica gel column chromatography (ethylacetate:hexane 1:5), to give 652 mg of the title compound as an ocheryellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 5.19 (2H, s), 6.23 (1H, d, J=9.2 Hz),6.70-7.71 (26H, m

Production Example II-19-c4-Fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl-amine

A total of 652 mg of{4-fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl}-carbamic acidbenzyl ester obtained in Production Example II-19-b was dissolved in 20ml of methanol, 652 mg of 10% palladium-carbon, and the mixture wassubjected to catalytic hydrogenation at room temperature at normalpressure. After stirring for 4 hours, the mixture was filtered throughCelite, and the filtrate was evaporated. The residue was purified andseparated by silica gel column chromatography (ethylacetate:hexane=1:5), to give 297 mg of the title compound.

¹H-NMR (400 MHz, CDCl₃) δ 3.54 (2H, brs), 6.09 (1H, d, J=8.8 Hz), 6.56(1H, t, J=8.8 Hz), 6.96-7.40 (17H, m), 7.51 (1H, d, J=10.4 Hz), 7.69(1H, d, J=7.6 Hz)

Production Example II-20-a6-Fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazole-5-carboxylic acid

A total of 496 mg of the title compound was obtained as ocher yellowcrystals by the procedure of Production Example II-18-a, except from 352mg of 6-fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acidobtained in Production Example II-5-f.

¹H-NMR (400 MHz, CDCl₃) δ 6.13 (1H, d, J=12.8 Hz), 6.96-7.78 (19H, m),8.73 (1H, d, J=10.4 Hz).

Production Example II-20-b{6-Fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl}-carbamic acidbenzyl ester

A total of 760 mg (crude purified product) was obtained by the procedureof Production Example II-19-b, except from 496 mg of6-fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid obtained inProduction Example II-20-a.

¹H-NMR (400 MHz, CDCl₃) δ 5.24 (2H, s) 6.09 (1H, d, J=12.0 Hz),6.80-6.86 (1H, brs), 7.00-7.07 (1H, m), 7.14-7.46 (22H, m), 7.54-7.60(1H, m), 7.65-7.73 (1H, m)

Production Example II-20-c6-Fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl-amine

A total of 185 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-19-c, except from 760mg of {6-fluoro-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl}-carbamicacid benzyl ester obtained in Production Example II-20-b.

¹H-NMR (400 MHz, CDCl₃) δ 3.65 (2H, brs), 6.06 (1H, d, J=12.0 Hz),6.97-7.05 (1H, m), 7.16-7.44 (17H, m), 7.54 (1H, d, J=6.0 Hz), 7.63 (1H,d, J=7.2 Hz)

Production Example II-214-Bromo-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl-amine

A total of 1.04 g of 3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-ylaminewas dissolved in 22.3 ml of dichloromethane, and 375 mg of sodiumhydrogencarbonate was added. Under ice-cooling and stirring, a solutionof 0.12 ml of bromine in 50 ml dichloromethane was added dropwise over50 minutes. After stirring for 2 hours while ice-cooling, saturatedaqueous sodium thiosulfate solution and the mixture was extracted withdiethyl ether. The resulting organic layer was washed with brine, driedover magnesium sulfate and the solvent was evaporated. The residue waspurified and separated by silica gel column chromatography (ethylacetate:hexane=1:5), to give 1.18 g of the title compound as a whitefoam.

¹H-NMR (400 MHz, CDCl₃) δ 3.97 (2H, brs), 6.31 (1H, d, J=8.8 Hz), 6.52(1H, d, J=8.8 Hz), 7.02-7.09 (1H, m), 7.18-7.43 (18H, m).

Production Example II-22-a5-Bromo-3-(3-fluoro-phenyl)-6-methoxy-1H-indazole

A total of 2.68 g of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-d, except from 5.05g of (5-bromo-2-fluoro-4-methoxy-phenyl)-(3-fluoro-phenyl)-methanoneobtained in Production Example II-1-b.

¹H-NMR (400 MHz, CDCl₃) δ 3.94 (3H, s), 6.85 (1H, s), 7.09-7.16 (1H, m),7.48 (1H, td, J=8.0, 6.0 Hz), 7.61-7.66 (1H, m), 7.68-7.74 (1H, m), 8.17(1H, s).

Production Example II-22-b5-Bromo-3-(3-fluoro-phenyl)-6-methoxy-1-trityl-1H-indazole

A total of 1.64 g of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-18-a, except from 914mg of 5-bromo-3-(3-fluoro-phenyl)-6-methoxy-1H-indazole obtained inProduction Example II-22-a.

¹H-NMR (400 MHz, CDCl₃) δ 3.38 (3H, s), 5.74 (1H, s), 7.00-7.06 (1H, m),7.14-7.36 (15H, m), 7.40 (1H, td, J=8.0, 6.0 Hz), 7.55 (1H, d, J=10.4Hz), 7.65 (1H, d, J=8.0 Hz), 8.15 (1H, s)

Production Example II-22-c3-(3-Fluoro-phenyl)-6-methoxy-1-trityl-1H-indazol-5-ylamine

A total of 526 mg of the title compound was obtained as an ocher yellowamorphous substance by the procedure of Production Example II-18-b,except from 674 mg of5-bromo-3-(3-fluoro-phenyl)-6-methoxy-1-trityl-1H-indazole obtained inProduction Example II-22-b.

¹H-NMR (400 MHz, CDCl₃) δ 3.37 (3H, s), 3.77 (2H, brs), 5.65 (1H, s),6.95-7.02 (1H, m), 7.17-7.40 (17H, m), 7.57 (1H, d, J=10.4 Hz), 7.67(1H, d, J=8.0 Hz)

Production Example II-233-(3-Fluoro-phenyl)-7-methyl-1-trityl-1H-indazol-5-ylamine

To a solution of 2.0 g of5-bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole obtained inProduction Example II-9-c in 20 ml toluene at room temperature wereadded 0.73 g of benzophenoneimine, 95 mg oftris(dibenzylideneacetone)(chloroform)dipalladium(0), 0.17 g of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 0.53 g of sodiumtert-butyrate, and the mixture was heated under reflux for one day. Themixture was diluted with water and ethyl acetate, and the organic layerwas sequentially washed with saturated aqueous ammonium chloridesolution and brine, dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was dissolved in 30 ml oftetrahydrofuran, 10 ml of 5 N hydrochloric acid was added at roomtemperature, and the mixture was stirred at the same temperature for 30minutes. The reaction mixture was neutralized with 5 N aqueous sodiumhydroxide solution and was extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate, andthe solvent was evaporated. The crude product was purified and separatedby silica gel column chromatography (ethyl acetate:n-hexane=1:10 to1:3), and the resulting obtained crystals were washed with diethylether, to give 0.86 g of the title compound as colorless crystals.

¹H-NMR (400 MHz, CDCl₃) δ 1.38 (3H, s), 3.61 (2H, brs), 6.45 (1H, dd,J=2.4, 0.8 Hz), 6.95 (1H, dt, J=0.8, 8.0 Hz), 7.12-7.31 (16H, m), 7.32(1H, dt, J=6.0, 8.0 Hz), 7.43 (1H, ddd, J=1.2, 2.4, 10.4 Hz), 7.55 (1H,dt, J=1.2, 8.0 Hz)

Production Example II-24-a3-Benzo[b]thiophen-2-yl-5-bromo-6-fluoro-1H-indazole

A total of 5.7 g ofbenzo[b]thiophen-2-yl-(5-bromo-2,4-difluorophenyl)methanone obtained inProduction Example II-16-a was allowed to react with hydrazinemonohydrate by the procedure of Production Example II-10-c and therebyyielded 0.6 g of the title compound as a colorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.34-7.43 (2H, m), 7.65 (1H, d, J=8.8 Hz),7.90 (1H, bd, J=7.6 Hz), 7.97 (1H, bd, J=7.6 Hz), 8.28 (1H, s), 8.65(1H, d, J=6.6 Hz), 13.50-13.60 (1H, bs).

Production Example II-24-b3-Benzo[b]thiophen-2-yl-5-bromo-6-fluoro-1-trityl-1H-indazole

A total of 350 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-18-a, except from 269mg of 3-benzo[b]thiophen-2-yl-5-bromo-6-fluoro-1H-indazole.

¹H-NMR (400 MHz, CDCl₃) δ 6.12 (1H, d, J=9.6 Hz), 7.18-7.38 (15H, m),7.73-7.84 (5H, m), 8.27 (1H, d, j=6.4 Hz).

Production Example II-24-c3-Benzo[b]thiophen-2-yl-6-fluoro-1-trityl-1H-indazol-5-ylamine

A total of 280 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-c, except from 350mg of 3-benzo[b]thiophen-2-yl-5-bromo-6-fluoro-1-trityl-1H-indazole.

¹H-NMR (400 MHz, DMSO-d₆) δ 5.88 (1H, d, J=12.4 Hz), 7.12-7.42 (17H, m),7.47 (1H, d, J=8.4 Hz), 7.82 (1H, s), 7.86 (1H, d, J=6.8 Hz), 7.93 (1H,d, J=6.8 Hz).

Production Example II-25-a5-Bromo-6-fluoro-3-naphthalen-2-yl-1H-indazole

A total of 7.0 g of(5-bromo-2,4-difluorophenyl)naphthalene-2-yl-methanone obtained inProduction Example II-17-a was allowed to react with hydrazinemonohydrate by the procedure of Production Example II-10-c and therebyyielded 1.5 g of the title compound as a colorless powder.

¹H-NMR (400 MHz, DMSO-d₆) δ 7.51-7.59 (2H, m), 7.63 (1H, d, J=9.0 Hz),7.93-7.96 (1H, m), 8.02 (1H, d, J=8.4 Hz), 8.14-8.18 (1H, m), 8.15 (1H,dd, J=1.6, 8.4 Hz), 8.56 (1H, d, J=1.6 Hz), 8.61 (1H, d, J=6.5 Hz),13.45-13.65 (1H, bs).

Production Example II-25-b5-Bromo-6-fluoro-3-naphthalen-2-yl-1-trityl-1H-indazole

A total of 1.22 g of the title compound was obtained as white crystalsby the procedure of Production Example II-18-a, except from 811 mg of5-bromo-6-fluoro-3-naphthalen-2-yl-1H-indazole.

¹H-NMR (400 MHz, CDCl₃) δ 6.17 (1H, d, J=10.0 Hz), 7.21-7.35 (15H, m),7.45-7.54 (2H, m), 7.81-7.97 (4H, m), 8.26-8.31 (2H, m).

Production Example II-25-c6-Fluoro-3-naphthalen-2-yl-1-trityl-1H-indazol-5-ylamine

A total of 970 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-c, except from 1.22g of 5-bromo-6-fluoro-3-naphthalen-2-yl-1-trityl-1H-indazole.

¹H-NMR (400 MHz, DMSO-d₆) δ 5.94 (1H, d, J=12.0 Hz), 7.20-7.40 (15H, m),7.47-7.59 (3H, m), 7.86-8.00 (4H, m), 8.31 (1H, s).

Production Example II-26C-{3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-methylamine

A total of 71 mg of lithium aluminium hydride was suspended in 4.7 ml oftetrahydrofuran, 249 mg of aluminium chloride was added underice-cooling, and the mixture was stirred for 10 minutes. To the reactionmixture was added 50 mg of3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carbonitrile obtained inProduction Example II-1-d, followed by stirring at room temperature for3 hours. The reaction mixture was ice-cooled, 27% aqueous ammonia wasadded and the mixture was filtrated through Celite. The filtrate wasevaporated, and the residue was purified and separated by silica gelcolumn chromatography (NH silica gel) (ethyl acetate), to give 108 mg ofthe title compound.

¹H-NMR (400 MHz, CD₃OD) δ 4.02 (3H, s), 4.25 (2H, s), 7.10-7.19 (2H, m),7.54 (1H, td, 8.0, 6.0 Hz), 7.63-7.69 (1H, m), 7.78 (1H, d, 8.0 Hz)

Production Example II-27-a4-Fluoro-3-(3-fluoro-benzoyl)-2-methoxy-benzonitrile

A total of 399 mg of the title compound was obtained as a pale yellowoil by the procedure of Production Example II-1-c, except from 2.07 g of(3-bromo1-6-fluoro-2-methoxy-phenyl)-(3-fluoro-phenyl)-methanoneobtained in Production Example II-2-b.

¹H-NMR (400 MHz, CDCl₃) δ 4.00 (3H, s), 7.01 (1H, t, J=8.0 Hz),7.32-7.76 (5H, m).

Production Example II-27-b3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carbonitrile

A total of 364 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-d, except from 399mg of 4-fluoro-3-(3-fluoro-benzoyl)-2-methoxy-benzonitrile obtained inProduction Example II-27-a.

¹H-NMR (400 MHz, CDCl₃) δ 3.94 (3H, s), 7.13-7.29 (2H, m), 7.47 (1H, td,J=8.0, 6.0 Hz), 7.52 (1H, d, J=8.8 Hz), 7.61-7.66 (1H, m), 7.67-7.72(1H, m).

Production Example II-27-cC-{3-(3-Fluoro-phenyl)-4-methoxy-1H-indazol-5-yl}-methylamine

A total of 25.8 mg of the title compound was obtained by the procedureof Production Example II-26, except from 50 mg of3-(3-fluoro-phenyl)-4-methoxy-1H-indazole-5-carbonitrile obtained inProduction Example II-27-b.

¹H-NMR (400 MHz, CD₃OD) δ 3.92 (5H, s), 7.10-7.18 (1H, m), 7.31 (1H, d,J=8.4 Hz), 7.43 (1H, d, J=8.4 Hz), 7.44-7.80 (3H, m). 7.47 (1H, td,J=8.0, 6.0 Hz), 7.52 (1H, d, J=8.8 Hz), 7.61-7.66 (1H, m), 7.67-7.72(1H, m).

Production Example II-28C-{6-Fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-methylamine

A total of 120 mg of the title compound was obtained as ocher yellowcrude crystals by the procedure of Production Example II-26, except from100 mg of 6-fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carbonitrileobtained in Production Example II-5-e.

¹H-NMR (400 MHz, CD₃OD) δ 4.34 (2H, s), 7.08-7.24 (1H, m), 7.42 (1H, d,J=10.6 Hz), 7.56 (1H, td, J=8.0, 6.0 Hz), 7.67-7.74 (1H, m), 7.80-7.85(1H, m), 8.26 (1H, d, J=7.2 Hz)

Production Example II-29C-(3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-methylamine

A total of 394 mg of the title compound was obtained as yellow crudecrystals by the procedure of Production Example II-26, except from 300mg of 3-benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carbonitrileobtained in Production Example II-16-c.

¹H-NMR (400 MHz, DMSO-d₆) δ 4.23 (2H, s), 7.37-7.46 (2H, m), 7.53 (1H,d, J=10.4 Hz), 7.89 (1H, d, J=7.2 Hz), 8.00 (1H, d, J=7.2 Hz), 8.23 (1H,s), 8.62 (1H, d, J=7.2 Hz).

Production Example II-30C-(3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-methylamine

A total of 495 mg of the title compound was obtained by the procedure ofProduction Example II-26, except from 300 mg of6-fluoro-3-naphthalen-2-yl-1H-indazole-5-carbonitrile obtained inProduction Example II-17-c.

¹H-NMR (400 MHz, DMSO-d₆) δ 4.23 (2H, s), 7.51 (1H, d, J=10.0 Hz),7.52-7.64 (2H, m), 7.97 (1H, d, J=8.8 Hz), 8.05 (1H, d, J=8.8 Hz),8.14-8.21 (2H, m), 8.62 (1H, d, J=7.2 Hz), 8.65 (1H, s).

Production Example II-31-a (6-Bromo-2,3-difluorophenyl)trimethylsilyl

In an atmosphere of nitrogen gas, 66.0 ml of a 1.57 M solution ofn-butyllithium in hexane was added to a solution of 18.2 ml ofN,N-diisopropylamine in 200 ml tetrahydrofuran at 0° C., and the mixturewas stirred at the same temperature for 10 minutes. After cooling to−78° C., a solution of 20.0 g of 1-bromo-3,4-difluorobenzene in 100 mltetrahydrofuran was added dropwise. After stirring at the sametemperature for 30 minutes, 32.9 ml of chlorotrimethylsilane was addeddropwise. The temperature was gradually raised to room temperature andthe mixture was stirred for one day. The reaction mixture was dilutedwith water and ethyl acetate. The organic layer was washed with brine,dried over anhydrous magnesium sulfate, and the solvent was evaporated.The crude product was purified and separated by silica gel columnchromatography (n-hexane), to give 20.3 g of the title compound as acolorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 0.47 (9H, s), 6.99 (1H, dt, J=9.6, 8.8 Hz),7.27 (1H, ddd, J=2.0, 4.0, 8.8 Hz).

Production Example II-31-b(5-Bromo-2,3-difluorophenyl)-(3-fluorophenyl)methanone

A total of 5.0 g of (6-bromo-2,3-difluorophenyl)trimethylsilyl wasallowed to react with 3-fluoro-benzaldehyde by the procedure ofProduction Example II-2-a. The resulting crude product was dissolved in50 ml of dimethylformamide and 5 ml of water, cesium fluoride was addedat room temperature, and the mixture was stirred at the same temperaturefor 3 hours. The reaction mixture was diluted with ethyl acetate, andthe organic layer was sequentially washed with saturated aqueousammonium chloride solution and brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated. The resulting crude product wasoxidized by the procedure of Production Example II-8-b, to give 4.52 gof the title compound as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ 7.34 (1H, ddt, J=1.2, 2.4, 8.0 Hz), 7.43 (1H,td, J=2.4, 5.2 Hz), 7.48 (1H, dt, J=5.2, 8.0 Hz), 7.50-7.58 (4H, m).

Production Example II-31-c 3,4-Difluoro-5-(3-fluorobenzoyl)benzonitrile

A total of 3.5 g of the title compound was obtained as a pale yellow oilby the procedure of Production Example II-9-d, except from 4.5 g of(5-bromo-2,3-difluorophenyl)-(3-fluorophenyl)methanone.

¹H-NMR (400 MHz, CDCl₃) δ 7.38 (1H, ddd, J=1.2, 2.4, 8.0 Hz), 7.47-7.55(3H, m), 7.63-7.71 (2H, m).

Production Example II-31-d7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carbonitrile

A total of 3.2 g of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-1-d, except from 3.5g of 3,4-difluoro-5-(3-fluorobenzoyl)benzonitrile.

¹H-NMR (400 MHz, CD₃OD) δ 7.20 (1H, dd, J=2.0, 8.0 Hz), 7.49 (1H, dd,J=1.2, 10.4 Hz), 7.56 (1H, dt, J=6.0, 8.0 Hz), 7.69 (1H, td, J=2.0, 10.4Hz), 7.78 (1H, d, J=8.0 Hz), 8.33 (1H, d, J=1.2 Hz).

Production Example II-31-e7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid

A total of 2.1 g of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-1-e, except from 3.2g of 7-fluoro-3-(3-fluorophenyl)-1H-indazole-5-carbonitrile.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.31 (1H, ddd, J=1.2, 2.4, 8.0 Hz), 7.62(1H, dt, J=6.0, 8.0 Hz), 7.70 (1H, dd, J=1.2, 11.6 Hz), 7.72 (1H, ddd,J=1.2, 2.4, 10.0 Hz), 7.81 (1H, dt, J=1.2, 8.0 Hz), 8.44 (1H, d, J=1.2Hz).

Production Example II-32-a(5-Bromo-2,3-difluorophenyl)naphthalen-2-ylmethanone

A total of 5.5 g of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-31-a, except from 5.0g of (6-bromo-2,3-difluorophenyl)trimethylsilyl.

¹H-NMR (400 MHz, CDCl₃) δ 7.48 (1H, td, J=2.0, 8.8 Hz), 7.52-7.59 (2H,m), 7.64 (1H, dt, J=1.2, 8.0 Hz), 7.88-7.98 (4H, m), 8.23 (1H, s).

Production Example II-32-b3,4-Difluoro-5-(naphthalen-2-carbonyl)benzonitrile

A total of 2.94 g of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-9-d, except from 5.5g of (5-bromo-2,3-difluorophenyl)naphthalen-2-ylmethanone.

¹H-NMR (400 MHz, CDCl₃) δ 7.58 (1H, dt, J=1.2, 8.0 Hz), 7.64-7.72 (3H,m), 7.90-7.96 (4H, m), 8.19 (1H, s).

Production Example II-32-c7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carbonitrile

A total of 2.60 g of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-1-d, except from 2.94g of 3,4-difluoro-5-(naphthalen-2-carbonyl)benzonitrile.

¹H-NMR (400 MHz, CD₃OD) δ 7.48-7.56 (3H, m), 7.88-7.93 (1H, m),7.98-8.11 (3H, m), 8.44 (1H, s), 8.47 (1H, d, J=0.8 Hz).

Production Example II-32-d7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid

To 1.0 g of 7-fluoro-3-naphthalen-2-yl-1H-indazole-5-carbonitrile weresequentially added 5.0 ml of glacial acetic acid, 5.0 ml of water and10.0 ml of concentrated sulfuric acid, and the mixture was stirred at120° C. for one day. After standing to cool, 20 ml of water was added tothe reaction mixture and the resulting crystals were collected byfiltration. The crystals were sequentially washed with water and diethylether, to give 1.0 g of the title compound as colorless crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.55-7.60 (2H, m), 7.71 (1H, dd, J=0.8, 11.2Hz), 7.96-7.99 (1H, m), 8.08-8.14 (3H, m), 8.51 (1H, s), 8.59 (1H, d,J=0.8 Hz).

Production Example II-33-a3-Benzo[b]thiophen-2-yl-4-fluoro-1-trityl-1H-5-indazolecarboxylic acid

To a solution of 149 mg of the coupling product(3-benzo[b]thiophen-2-yl-4-fluoro-1-trityl-1H-5-indazolecarboxylic acidmethyl ester) obtained in Production Example II-13-f in a solventmixture of 4 ml of tetrahydrofuran and 1 ml of methanol was added 0.5 mlof 5 N aqueous sodium hydroxide solution, and the mixture was stirred at50° C. for 2 hours. To the reaction mixture was added 3 ml of 1 Nhydrochloric acid and the mixture was extracted with 20 ml of ethylacetate. The organic layer was sequentially washed with water and brine,dried over anhydrous magnesium sulfate, and the solvent was evaporated,to give 145 mg of the title compound as yellow crystals.

¹H-NMR (400 MHz, DMSO-D₆) δ 6.29 (1H, dd J=1.2, 8.8 Hz), 7.14-7.23 (6H,m), 7.27-7.42 (11H, m), 7.55 (1H, t, J=8.8 Hz), 7.91-7.97 (2H, m), 8.02(1H, s), 13.19 (1H, s).

Production Example II-33-b{3-Benzo[b]thiophen-2-yl-4-fluoro-1-trityl-1H-indazol-5-yl}carbamic acidbenzyl ester

A total of 73 mg of the title compound was obtained as a colorlessviscous oil by the procedure of Production Example II-19-b, except from143 mg of3-benzo[b]thiophen-2-yl-4-fluoro-1-trityl-1H-5-indazolecarboxylic acidobtained in Production Example II-33-a.

¹H-NMR (400 MHz, DMSO-D₆) δ 5.14 (2H, s), 6.23 (1H, d, J=8.8 Hz),7.13-7.45 (23H, m), 7.89-7.99 (3H, m), 9.43 (1H, s).

Production Example II-33-c3-Benzo[b]thiophen-2-yl-4-fluoro-1-trityl-1H-indazol-5-ylamine

A total of 52 mg of the title compound was obtained as bright yellowcrystals by the procedure of Production Example II-19-c, except from 68mg of{3-benzo[b]thiophen-2-yl-4-fluoro-1-trityl-1H-indazol-5-yl}carbamic acidbenzyl ester produced in Production Example II-33-b.

¹H-NMR (400 MHz, DMSO-D₆) δ 5.00 (2H, s), 6.00 (1H, d, J=8.8 Hz), 6.69(1H, t, J=8.8 Hz), 7.10-7.40 (17H, m), 7.83-7.93 (3H, m)

Production Example II-34-a4-Fluoro-3-naphthalen-2-yl-1-trityl-1H-5-indazolecarboxylic acid

A total of 127 mg of the title compound was obtained as yellow crystalsby the procedure of Production Example II-33-a, except from 139 mg ofthe coupling product(4-fluoro-3-naphthalen-2-yl-1-trityl-1H-5-indazolecarboxylic acid methylester) produced in Production Example II-14-a.

¹H-NMR (400 MHz, DMSO-D₆) δ 6.34 (1H, dd, J=0.8, 8.8 Hz), 7.18-7.40(16H, m), 7.50-7.60 (2H, m), 7.84 (1H, d, J=8.4 Hz), 7.93-8.08 (3H, m),8.30 (1H, s), 13.09 (1H, s)

Production Example II-34-b{4-Fluoro-3-naphthalen-2-yl-1-trityl-1H-indazol-5-yl}carbamic acidbenzyl ester

A total of 54 mg of the title compound was obtained as a colorlessviscous oil by the procedure of Production Example II-19-b, except from125 mg of 4-fluoro-3-naphthalen-2-yl-1-trityl-1H-5-indazolecarboxylicacid obtained in Production Example II-34-a.

¹H-NMR (400 MHz, DMSO-D₆) 5.11 (2H, s), 6.27 (1H, d, J=8.8 Hz),7.20-7.45 (2H, m), 7.52-7.58 (2H, m), 7.83 (1H, d, J=8.4 Hz), 7.92-8.00(3H, m), 8.26 (1H, s), 9.35 (1H, s).

Production Example II-34-c4-Fluoro-3-naphthalen-2-yl-1-trityl-1H-indazol-5-ylamine

A total of 41 mg of the title compound was obtained as pale red crystalsby the procedure of Production Example II-19-c, except from 54 mg of{4-fluoro-3-naphthalen-2-yl-1-trityl-1H-indazol-5-yl}carbamic acidbenzyl ester produced in Production Example II-34-b.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.92 (2H, s), 6.07 (1H, d, J=8.8 Hz), 6.70(1H, t, J=8.8 Hz), 7.20-7.40 (15H, m), 7.51-7.58 (2H, m), 7.86 (1H, d,J=8.8 Hz), 7.91-7.98 (3H, m) 8.28 (1H, s)

Production Example II-35-a 1-Bromo-4-fluoro-2-propoxy-benzene

A total of 5 g of 2-bromo-5-fluoro-phenol was dissolved in 66 ml ofN,N-dimethylformamide. Under ice-cooling, 5.42 g of potassium carbonateand 3.07 ml of iodopropane were added, and the mixture was stirred atroom temperature for 10 hours. Water was added to the reaction mixture,followed by extracting with diethyl ether. The resulting organic layerwas washed with brine, dried over magnesium sulfate and the solvent wasevaporated, to give 8.29 g of the title compound as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 1.08 (3H, t, J=7.2 Hz), 1.80-1.93 (2H, m),3.95 (2H, t, J=6.0 Hz), 6.54 (1H, td, J=8.8, 2.4 Hz), 6.61 (1H, dd,J=10.8, 2.4 Hz), 7.44 (1H, dd, J=8.8, 6.0 Hz)

Production Example II-35-bBenzo[b]furan-2-yl-(3-bromo-6-fluoro-2-propoxy-phenyl)-methanol

A total of 5.59 g of the title compound was obtained as a pale yellowoil by the procedure of Production Example II-2-a, except from 3 g of1-bromo-4-fluoro-2-propoxy-benzene.

¹H-NMR (400 MHz, CDCl₃) δ 0.96 (3H, t, J=7.2 Hz), 1.80-1.93 (2H, m),3.95 (2H, t, J=6.4 Hz), 6.29 (1H, d, J=9.2 Hz), 6.84 (1H, t, J=9.2 Hz),7.16-7.76 (6H, m)

Production Example II-35-cBenzo[b]furan-2-yl-(3-bromo-6-fluoro-2-propoxy-phenyl)-methanone

A total of 1.46 g of the title compound was obtained as a yellow oil bythe procedure of Production Example II-2-b, except from 5.59 g ofbenzo[b]furan-2-yl-(3-bromo-6-fluoro-2-propoxy-phenyl)-methanol.

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (3H, t, J=7.2 Hz), 1.61-1.72 (2H, m),3.96 (2H, t, J=6.8 Hz), 6.87 (1H, t, J=9.2 Hz), 7.29-7.70 (6H, m)

Production Example II-35-d3-Benzo[b]furan-2-yl-5-bromo-4-propoxy-1H-indazole

A total of 801 mg of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-10-c, except from1.46 g ofbenzo[b]furan-2-yl-(3-bromo-6-fluoro-2-propoxy-phenyl)-methanone.

¹H-NMR (400 MHz, DMSO-D₆) δ 0.92 (3H, t, J=7.2 Hz), 1.65-1.78 (2H, m),3.77 (2H, t, J=6.4 Hz), 7.28 (1H, t, J=7.2 Hz), 7.33-7.38 (1H, m), 7.36(1H, d, J=8.8 Hz), 7.44 (1H, s), 7.59 (1H, d, J=8.8 Hz), 7.64 (1H, d,J=8.8 Hz), 7.72 (1H, d, J=8.8 Hz)

Production Example II-35-e3-Benzo[b]furan-2-yl-4-propoxy-1H-indazole-5-carboxylic acid

A total of 45 mg of the title compound was obtained by the procedure ofProduction Example II-10-d, except from 326 mg of3-benzo[b]furan-2-yl-5-bromo-4-propoxy-1H-indazole.

¹H-NMR (400 MHz, CD₃OD) δ 0.86 (3H, t, J=7.2 Hz), 1.70-1.81 (2H, m),3.95 (2H, t, J=7.2 Hz), 7.27 (1H, t, J=7.6 Hz), 7.32-7.38 (2H, m), 7.53(1H, s), 7.58 (1H, d, J=7.6 Hz), 7.68 (1H, d, J=7.6 Hz), 7.89 (1H, d,J=8.8 Hz)

Production Example II-36-a7-Fluoro-3-(3-fluorophenyl)-1-trityl-1H-indazole-5-carboxylic acid

A total of 1.4 g of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-9-c, except from 1.0g of 7-fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid obtainedin Production Example II-31-e.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.10-7.13 (5H, m), 7.25-7.35 (1H, m), 7.45(1H, d, J=12.0 Hz), 7.53 (1H, d, J=8.0 Hz), 7.59 (1H, dt, J=6.4, 8.0Hz), 7.69 (1H, d, J=8.0 Hz), 8.44 (1H, d, J=1.2 Hz).

Production Example II-36-b7-Fluoro-3-(3-fluorophenyl)-1-trityl-1H-indazol-5-ylamine

To a solution of 1.0 g of7-fluoro-3-(3-fluorophenyl)-1-trityl-1H-indazole-5-carboxylic acid in 20ml toluene at room temperature were added 0.40 ml of triethylamine and0.46 ml of diphenylphosphoryl azide, the mixture was stirred at the sametemperature for 2 hours and at 120° C. for 1.5 hours. To the reactionmixture was added 1.0 ml of benzyl alcohol, followed by stirring at 120°C. for 1.5 hours. After cooling to room temperature, water was added tothe reaction mixture was and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and the solvent wasevaporated. To a solution of the resulting crude product in a solventmixture of 20 ml of methanol and 10 ml of tetrahydrofuran was added 1.0g of 10% palladium-carbon at room temperature, and the mixture wassubjected to catalytic hydrogenation at the same temperature and atnormal atmospheric pressure. After stirring for 4 hours, the reactionmixture was filtrated through Celite, the filtrate was evaporated, andthe residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:5), to give 540 mg of the titlecompound.

¹H-NMR (400 MHz, DMSO-D₆) δ 5.19 (2H, d, J=8.4 Hz), 6.33 (1H, dd, J=1.6,14.0 Hz), 6.95 (1H, d, J=1.6 Hz), 7.08-7.41 (16H, m), 7.42 (1H, ddd,J=1.2, 1.6, 10.0 Hz), 7.49 (1H, dt, J=6.0, 10.0 Hz), 7.56 (1H, d, J=8.0Hz).

Production Example II-37-a7-Fluoro-3-naphthalen-2-yl-1-trityl-1H-indazole-5-carboxylic acid

A total of 840 mg of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-9-c, except from 500mg of 7-fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid obtainedin Production Example II-32-d.

¹H-NMR (400 MHz, DMSO-D₆) δ 7.14-7.36 (15H, m), 7.46 (1H, dd, J=1.2,12.4 Hz), 7.55-7.58 (2H, m), 7.85 (1H, dd, J=2.0, 8.8 Hz), 7.92-7.96(1H, m), 8.03 (1H, d, J=1.2, 8.8 Hz), 8.06-8.09 (1H, m), 8.41 (1H, s),8.56 (1H, d, J=1.2 Hz).

Production Example II-37-b7-Fluoro-3-naphthalen-2-yl-1-trityl-1H-indazol-5-ylamine

A total of 320 mg of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-36-b, except from 870mg of 7-fluoro-3-naphthalen-2-yl-1-trityl-1H-indazole-5-carboxylic acid.

¹H-NMR (400 MHz, DMSO-D₆) δ 5.18 (2H, d, J=8.4 Hz), 6.36 (1H, dd, J=1.6,9.6 Hz), 7.11 (1H, d, J=1.6 Hz), 7.22-7.33 (15H, m), 7.50 (1H, dt,J=1.2, 6.8 Hz), 7.54 (1H, dt, J=1.2, 6.8 Hz), 7.80 (1H, dd, J=1.2, 8.8Hz), 7.88-7.97 (3H, m), 8.27 (1H, s).

Production Example II-38-a(4-Methoxy-3-naphthalen-2-yl-1-trityl-1H-indazol-5-yl)-carbamic acidbenzyl ester

493 mg of 4-methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidobtained in Production Example II-10-d was dissolved in 10 ml ofdimethylformamide. Under ice-cooling and stirring, 136 mg of sodiumhydride (content 60%) was added thereto. After stirring for 15 minutes,454 mg of triphenylmethyl chloride was added. After stirring at roomtemperature for 2 hours, the reaction mixture was diluted with saturatedaqueous ammonium chloride solution and was extracted with ethyl acetate.The resulting organic layer was washed with brine, dried over magnesiumsulfate and the solvent was evaporated. The residue was purified andseparated by silica gel column chromatography(chloroform:methanol=20:1), to give 728 mg of a trityl derivative as anocher yellow amorphous substance. The resulting compound was dissolvedin 10 ml of toluene, and 0.27 ml of triethylamine and 0.28 ml ofdiphenylphosphoryl azide were added to the solution at room temperatureunder stirring. The mixture was stirred at room temperature for 2 hoursand at 120° C. for further 1.5 hours. 0.67 ml of benzyl alcohol wasadded thereto, followed by stirring at 120° C. for 1.5 hours. Aftercooling to room temperature, water was added thereto and the mixture wasextracted with ethyl acetate. The resulting organic layer was washedwith brine, dried over magnesium sulfate and the solvent was evaporated.The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:4), to give 466 mg of the titlecompound as an ocher yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.38 (3H, s), 5.20 (2H, s), 6.29 (1H, d, J=9.6Hz), 7.17-7.49 (23H, m), 7.84-7.90 (3H, m), 8.02 (1H, d, J=7.2 Hz), 8.44(1H, s).

Production Example II-38-b4-Methoxy-3-naphthalen-2-yl-1-trityl-1H-indazol-5-ylamine

466 mg of(4-methoxy-3-naphthalen-2-yl-1-trityl-1H-indazol-5-yl)-carbamic acidbenzyl ester obtained in Production Example II-38-a was dissolved in 20ml of a 1:1 solvent mixture of ethyl acetate and methanol. 300 mg of 10%palladium-carbon was added and the mixture was subjected to catalytichydrogenation at room temperature and normal atmospheric pressure. Thereaction mixture was filtered through Celite, and the solvent wasremoved, to give 252 mg of the title compound.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.37 (3H, s), 6.21 (1H, d, J=8.8 Hz), 6.81(1H, d, J=9.2 Hz), 7.06 (1H, t, J=7.6 Hz), 7.18-7.61 (17H, m), 7.97-8.01(3H, m), 8.46 (1H, s).

Production Example II-39-a(3-Benzo[b]thiophen-2-yl-4-methoxy-1-trityl-1H-indazol-5-yl)carbamicacid benzyl ester

548 mg of 3-benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylicacid obtained in Production Example II-12-d was dissolved in 10 ml ofdimethylformamide. Under ice-cooling and stirring, 149 mg of sodiumhydride (content 60%) was added and the mixture was stirred for 15minutes. Then, 495 mg of triphenylmethyl chloride was added and themixture was stirred at room temperature for 2 hours. Then, saturatedaqueous ammonium chloride solution was added and the mixture wasextracted with ethyl acetate. The resulting organic layer was washedwith saturated aqueous sodium chloride solution, dried over magnesiumsulfate and the solvent was evaporated. The residue was purified andseparated by silica gel column chromatography(chloroform:methanol=20:1), to give 854 mg of a trityl derivative as anocher yellow amorphous substance. The resulting compound was dissolvedin 10 ml of toluene, 0.32 ml of triethylamine and 0.36 ml ofdiphenylphosphoryl azide were added, followed by stirring at roomtemperature for 2 hours and at 120° C. for 1.5 hours. Then, 0.78 ml ofbenzyl alcohol was added, followed by stirring at 120° C. for 1.5 hours.After cooling to room temperature, water was added and the mixture wasextracted with ethyl acetate. The resulting organic layer was washedwith brine, dried over magnesium sulfate and the solvent was evaporated.The residue was purified and separated by silica gel columnchromatography (ethyl acetate:hexane=1:4), to give 939 mg of the titlecompound as an ocher yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ 3.70 (3H, s), 5.20 (2H, s), 6.23 (1H, d, J=9.2Hz), 7.21-7.39 (23H, m), 7.78 (2H, d, J=8.4 Hz), 8.01 (1H, s).

Production Example II-39-b3-Benzo[b]thiophen-2-yl-4-methoxy-1-trityl-1H-indazol-5-ylamine

A total of 939 mg of(3-benzo[b]thiophen-2-yl-4-methoxy-1-trityl-1H-indazol-5-yl)-carbamicacid benzyl ester obtained in Production Example II-39-a was dissolvedin 20 ml of a 2:1 solvent mixture of ethyl acetate and methanol. 300 mgof 20% palladium hydroxide-carbon was added thereto, and the mixture wassubjected to catalytic hydrogenation at room temperature and at normalatmospheric pressure in the presence of. The reaction mixture wasfiltrated through Celite, and the solvent was removed, to give 458 mg ofthe title compound.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.63 (3H, s), 6.02 (1H, d, J=8.8 Hz), 6.68(1H, d, J=8.8 Hz), 7.00 (1H, t, J=7.2 Hz), 7.10-7.36 (16H, m), 7.87 (2H,t, J=8.0 Hz), 8.07 (1H, s).

Production Example II-40C-(7-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)methylamine

A total of 260 mg of the title compound was obtained as colorlesscrystals by the procedure of Production Example II-26, except from 280mg of 7-fluoro-3-naphthalen-2-yl-1H-indazole-5-carbonitrile obtained inProduction Example II-32-c.

¹H-NMR (400 MHz, DMSO-D₆) δ 3.86 (2H, s), 7.28 (1H, d, J=12.0 Hz),7.50-7.60 (2H, m), 7.95 (1H, d, J=8.4 Hz), 7.98 (1H, s), 8.03 (1H, d,J=8.4 Hz), 8.10 (1H, d, J=8.4 Hz), 8.16 (1H, dd, J=1.6, 8.4 Hz), 8.54(1H, s).

Production Example II-41-a 5-Bromo-2-fluoro-4-methoxy-benzaldehyde

8.4 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in ProductionExample II-1-a was dissolved in 200 ml of dichloromethane. 21 ml oftitanium tetrachloride and 5.6 ml of dichloromethyl methyl ether wereadded at 0° C. in nitrogen atmosphere, followed by stirring at roomtemperature for 4.5 hours. Then, the reaction mixture was graduallypoured onto ice-water, and extracted with diethyl ether for two times.The organic layer was sequentially washed with each one portion ofwater, saturated aqueous sodium hydrogencarbonate solution and water,dried over magnesium sulfate and the solvent was evaporated, to give9.44 g of the title compound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ 3.97 (3H, s), 6.67 (1H, d, J=12.0 Hz), 8.05(1H, d, J=7.6 Hz), 10.15 (1H, s)

Production Example II-41-b 4-Fluoro-5-formyl-2-methoxy-benzonitrile

5.33 g of 5-bromo-2-fluoro-4-methoxy-benzaldehyde was dissolved in 73 mlof 1-methyl-2-pyrrolidone, 2.46 g of copper cyanide was added understirring at 180° C. for 5.5 hours. After cooling to room temperature,water was added to the reaction mixture. The mixture was extracted withethyl acetate and filtered through Celite. Then, the resulting organiclayer was washed with water and brine, dried over magnesium sulfate andthe solvent was evaporated. The residue was purified and separated bysilica gel column chromatography, to give 0.983 g of the title compoundas pale yellow crystals.

¹H-NMR (400 MHz, CDCl₃) δ 4.03 (3H, s), 6.76 (1H, d, J=12.0 Hz), 8.14(1H, d, J=7.2 Hz), 10.17 (1H, s)

Production Example II-41-c 6-Methoxy-1H-indazole-5-carbonitrile

A total of 0.915 g of the title compound was obtained as pale yellowcrystals by the procedure of Production Example II-1-d, except from0.983 g of 4-fluoro-5-formyl-2-methoxy-benzonitrile.

¹H-NMR (400 MHz, CD₃OD) δ 3.99 (3H, s), 7.10 (1H, s), 8.06 (1H, s), 8.15(1H, s).

Production Example II-41-d 3-Bromo-6-methoxy-1H-indazole-5-carbonitrile

A total of 1.2 g of the title compound was obtained as yellow crystalsby the procedure of Production Example II-13-d, except from 0.915 g of6-methoxy-1H-indazole-5-carbonitrile.

¹H-NMR (400 MHz, CD₃OD) δ 4.00 (3H, s), 7.10 (1H, s), 7.97 (1H, s)

Production Example II-41-e3-Bromo-6-methoxy-1-trityl-1H-indazole-5-carbonitrile

A total of 2.41 g of the title compound was obtained as brown crystalsby the procedure of Production Example II-9-c, except from 1.2 g of3-bromo-6-methoxy-1H-indazole-5-carbonitrile.

¹H-NMR (400 MHz, CDCl₃) δ 3.36 (3H, s), 5.60 (1H, s), 7.14-7.17 (5H, m),7.24-7.32 (10H, m), 7.81 (1H, s)

Production Example II-41-f6-Methoxy-3-naphthalen-2-yl-1-trityl-1H-indazole-5-carbonitrile

A total of 249 mg of the title compound (a Suzuki coupling product) wasobtained as white crystals by the procedure of Production ExampleII-13-f, except from 600 mg of3-bromo-6-methoxy-1-trityl-1H-indazole-5-carbonitrile and 260 mg of2-naphthaleneboronic acid.

¹H-NMR (400 MHz, CDCl₃) δ 3.39 (3H, s), 5.73 (1H, s), 7.14-7.33 (16H,m), 7.49-7.53 (2H, m), 7.84-7.95 (3H, m), 8.28 (1H, s), 8.38 (1H, s)

Production Example II-41-g6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid

A total of 104.3 mg of the title compound was obtained as brown crystalsby the procedure of Production Example II-1-e, except from 249 mg of6-methoxy-3-naphthalen-2-yl-1-trityl-1H-indazole-5-carbonitrile.

¹H-NMR (400 MHz, CD₃OD) δ 4.02 (3H, s), 7.15 (1H, s), 7.53-7.58 (2H, m),7.91-7.94 (1H, m), 8.00-8.06 (3H, m), 8.41 (1H, s), 8.66 (1H, s)

ESI-MS: m/z=319 (M+H)⁺

Production Example II-42-a3-Benzo[b]thiophen-2-yl-6-methoxy-1-trityl-1H-indazole-5-carbonitrile

A total of 292.5 mg of the title compound (a Suzuki coupling product)was obtained as white crystals by the procedure of Production ExampleII-13-f, except from 600 mg of3-bromo-6-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained inProduction Example II-41-e and 269 mg of 2-benzo[b]thiopheneboronicacid.

¹H-NMR (400 MHz, CDCl₃) δ 3.37 (3H, s), 5.69 (1H, s), 7.14-7.89 (20H,m), 8.34 (1H, s)

Production Example II-42-b3-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acid

A total of 133.6 mg of the title compound was obtained as brown crystalsby the procedure of Production Example II-1-e, except from 292.5 mg of3-benzo[b]thiophen-2-yl-6-methoxy-1-trityl-1H-indazole-5-carbonitrile.

¹H-NMR (400 MHz, CD₃OD) δ 4.00 (3H, s), 7.12 (1H, s), 7.34-7.40 (2H, m),7.88-7.92 (2H, m), 7.95 (1H, s), 8.69 (1H, s)

ESI-MS: m/z=325 (M+H)⁺

Production Example II-43-a3-Benzo[b]furan-2-yl-4-fluoro-1-trityl-1H-5-indazolecarboxylic acid

A total of 146 mg of the title compound was obtained as bright yellowcrystals by the hydrolysis procedure of Production Example II-33-a,except from 152 mg of3-benzo[b]furan-2-yl-4-fluoro-1-trityl-1H-5-indazolecarboxylic acidmethyl ester obtained in the coupling reaction of Production ExampleII-15-a.

¹H-NMR (400 MHz, DMSO-D₆) δ 6.36 (1H, d J=8.8 Hz), 7.18-7.40 (17H, m),7.44 (1H, s), 7.56 (1H, dd, J=7.2, 8.8 Hz), 7.63 (1H, d, J=8.0 Hz), 7.74(1H, d, J=7.6 Hz), 13.19 (1H, s).

Production Example II-43-b{3-Benzo[b]furan-2-yl-4-fluoro-1-trityl-1H-indazol-5-yl}carbamic acidbenzyl ester

A total of 26 mg of the title compound was obtained as a white amorphouspowder by the procedure of Production Example II-19-b, except from 144mg of 3-benzo[b]furan-2-yl-4-fluoro-1-trityl-1H-5-indazolecarboxylicacid obtained in Production Example II-43-a.

¹H-NMR (400 MHz, DMSO-D₆) δ 5.12 (2H, s), 6.28 (1H, d, J=9.2 Hz),7.16-7.44 (24H, m), 7.60 (1H, d, J=8.4 Hz), 7.73 (1H, d, J=8.0 Hz), 9.40(1H, s).

Production Example II-43-c3-Benzo[b]furan-2-yl-4-fluoro-1-trityl-1H-indazol-5-ylamine

A total of 24 mg of the title compound was obtained as a pale yellowviscous oily substance by the procedure of Production Example II-19-c,except from 26 mg of{3-benzo[b]furan-2-yl-4-fluoro-1-trityl-1H-indazol-5-yl}carbamic acidbenzyl ester obtained in Production Example II-43-b.

¹H-NMR (400 MHz, DMSO-D₆) δ 4.99 (2H, s), 6.06 (1H, d, J=8.8 Hz), 6.69(1H, t, J=8.8 Hz), 7.14-7.41 (18H, m), 7.57 (1H, d, J=8.0 Hz), 7.69 (1H,d, J=7.6 Hz)

Typical synthesis processes for the compounds according to the exampleswill be illustrated below.

Synthesis Process II-A

Each of the carboxylic acids produced in Production Examples II wasdissolved in dimethylformamide and was pipetted into test tubes. To eachtest tube were sequentially added 1.2 equivalents of a 1 M solution ofvarious of amines in dimethylformamide, 1.2 equivalents of a 1 Msolution of 1-hydroxybenzotriazole monohydrate in dimethylformamide, 4equivalents of diisopropylethylamine, and 2 equivalents of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (i.e.,WSC.HCl), each of which had been previously prepared. The mixture wasstirred at room temperature overnight. The reaction mixture was purifiedand separated by LC-MS (developing solvent; acetonitrile solutioncontaining 0.1% trifluoroacetic acid:aqueous solution containing 0.1%trifluoroacetic acid=20:80 to 80:20, 10 minute-cycle, flow rate; 30ml/min, column; YMC Combiprep ODS-AM, 20 mmΦ×50 mm (Long)), to give thecompounds according to Examples.

Synthesis Process II-B

Each of the amines produced in Production Examples II was dissolved indimethylformamide and was pipetted into test tubes. To each test tubewere sequentially added 1.2 equivalents of a 1 M solution of any ofcarboxylic acids in dimethylformamide, 1.2 equivalents of a 1 M solutionof 1-hydroxybenzotriazole monohydrate in dimethylformamide, 4equivalents of diisopropylethylamine and 2 equivalents of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (i.e.,WSC.HCl), each of which had been previously prepared. The mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith water and was extracted with ethyl acetate. The extract wasair-dried by blowing nitrogen gas to remove the solvent, and the residuewas treated with a 1:5 mixture solution of trifluoroacetic acid anddichloromethane, and the mixture was stirred at room temperatureovernight. The reaction mixture was air-dried by blowing nitrogen gas toremove the solvent, and the residue was dissolved in dimethylformamide.Each was purified and separated by LC-MS under the same conditions as inSynthesis Process II-A and thereby yielded the compounds according toExamples.

Synthesis Process II-C

Each of the amines produced in Production Examples II was dissolved indimethylformamide and was pipetted into test tubes. To each test tubewere sequentially added 1.2 equivalents of a 1 M solution of any ofcarboxylic acids in dimethylformamide, 1.2 equivalents of a 1 M solutionof 1-hydroxybenzotriazole monohydrate in dimethylformamide, 4equivalents of diisopropylethylamine and 2 equivalents of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (i.e.,WSC.HCl), each of which had been previously prepared. The mixture wasstirred at room temperature overnight. Each mixture was purified andseparated by LC-MS under the same conditions as in Synthesis ProcessII-A, to give the compounds according to Examples.

Synthesis Process II-D

Each of the amines produced in Production Examples II was dissolved indichloromethane and was pipetted into test tubes (1 ml each). To eachtest tube were sequentially added 3 equivalents of triethylamine and 2equivalents of any of sulfonyl chlorides, and the mixture was stirred atroom temperature overnight. The reaction mixture was treated with 0.2 mlof trifluoroacetic acid under stirring at room temperature overnight.The reaction mixture was air-dried by blowing nitrogen gas, and theresidue was dissolved in dimethylformamide. Each was purified andseparated by LC-MS under the same conditions as in Synthesis ProcessII-A, to give the compounds according to Examples.

Synthesis Process II-E

Each of the amines produced in Production Examples II was dissolved in 1ml of dichloromethane. Each solution was treated with 0.2 ml oftrifluoroacetic acid under stirring at room temperature overnight. Thereaction mixture was air-dried by blowing nitrogen gas, and the residuewas dissolved in dimethylformamide. Each was purified and separated byLC-MS under the same conditions as in Synthesis Process II-A, to givethe compounds according to Examples.

The compounds according to Examples II-1 to II-152 were synthesized bySynthesis Process II-A using the carboxylic acids produced in ProductionExamples II-1 to II-17.

Example II-1 3-(3-Fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 366 MH⁺

Example II-2 3-(3-Fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid(2-acetylamino-ethyl)-amide

MS (ESI) m/z 371 MH⁺

Example II-3 3-(3-Fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 372 MH⁺

Example II-4 3-(3-Fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylic acid(pyridin-3-ylmethyl)-amide

MS (ESI) m/z 377 MH⁺

Example II-5 3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 366 MH⁺

Example II-6 3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carboxylic acid(2-acetylamino-ethyl)-amide

MS (ESI) m/z 371 MH⁺

Example II-7 3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 372 MH⁺

Example II-6 3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carboxylic acid(pyridin-3-ylmethyl)-amide

MS (ESI) m/z 377 MH⁺

Example II-9 3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 326 MH⁺

Example II-10 3-(3-Fluoro-phenyl)-6-methoxy-1H-indazole-5-carboxylicacid cyclopropylamide

MS (ESI) m/z 326 MH⁺

Example II-11 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 314 MH⁺

Example II-12 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(2-acetylamino-ethyl)-amide

MS (ESI) m/z 359 MH⁺

Example II-13 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(2-dimethylamino-ethyl)-amide

MS (ESI) m/z 345 MH⁺

Example II-14 3-(3-Fluoro-phenyl)-6-hydroxy-1H-indazole-5-carboxylicacid cyclopropylamide

MS (ESI) m/z 312 MH⁺

Example II-15 3-(3-Fluoro-phenyl)-6-hydroxy-1H-indazole-5-carboxylicacid (furan-2-ylmethyl)-amide

MS (ESI) m/z 352 MH⁺

Example II-16 3-(3-Fluoro-phenyl)-6-hydroxy-1H-indazole-5-carboxylicacid (2-acetylamino-ethyl)-amide

MS (ESI) m/z 357 MH⁺

Example II-17 3-(3-Fluoro-phenyl)-6-hydroxy-1H-indazole-5-carboxylicacid (pyridin-3-ylmethyl)-amide

MS (ESI) m/z 363 MH⁺

Example II-18 3-(3-Fluoro-phenyl)-6-hydroxy-1H-indazole-5-carboxylicacid (2-dimethylamino-ethyl)-amide

MS (ESI) m/z 343 MH⁺

Example II-19 3-(3-Fluoro-phenyl)-6-hydroxy-1H-indazole-5-carboxylicacid (1H-imidazol-4-ylmethyl)-amide

MS (ESI) m/z 352 MH⁺

Example II-20 6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 354 MH⁺

Example II-21 6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(2-acetylamino-ethyl)-amide

MS (ESI) m/z 359 MH⁺

Example II-22 6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(pyridin-3-ylmethyl)-amide

MS (ESI) m/z 365 MH⁺

Example II-23 6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(2-dimethylamino-ethyl)-amide

MS (ESI) m/z 345 MH⁺

Example II-24 6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(1H-imidazol-4-ylmethyl)-amide

MS (ESI) m/z 354 MH⁺

Example II-25 6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 314 MH⁺

Example II-26 3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carboxylicacid 3-methoxy-benzylamide

MS (ESI) m/z 406 MH⁺

Example II-27 6-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid3-methoxy-benzylamide

MS (ESI) m/z 394 MH⁺

Example II-28 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid3-methoxy-benzylamide

MS (ESI) m/z 390 MH⁺

Example II-29 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid3-methoxy-benzylamide

MS (ESI) m/z 394 MH⁺

Example II-30 3-(3-Fluoro-phenyl)-4-methoxy-1H-indazole-5-carboxylicacid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

MS (ESI) m/z 411 MH⁺

Example II-31 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

MS (ESI) m/z 395 MH⁺

Example II-32 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

MS (ESI) m/z 399 MH⁺

Example II-33 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid(2-thiophen-2-yl-ethyl)-amide

MS (ESI) m/z 380 MH⁺

Example II-34 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(2-thiophen-2-yl-ethyl)-amide

MS (ESI) m/z 384 MH⁺

Example II-35 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(tetrahydrofuran-2-ylmethyl)-amide

MS (ESI) m/z 358 MH⁺

Example II-36 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(2-ethoxy-ethyl)-amide

MS (ESI) m/z 346 MH⁺

Example II-37 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid(2-ethoxy-ethyl)-amide

MS (ESI) m/z 342 MH⁺

Example II-38 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acidcyclopropylmethyl-amide

MS (ESI) m/z 324 MH⁺

Example II-39 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid(2-methylsulfanyl-ethyl)-amide

MS (ESI) m/z 344 MH⁺

Example II-40 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(2-methylsulfanyl-ethyl)-amide

MS (ESI) m/z 348 MH⁺

Example II-41 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid[(1S)-1-carbamoyl-ethyl]-amide

MS (ESI) m/z 341 MH⁺

Example II-42 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid[(1S)-1-carbamoyl-ethyl]-amide

MS (ESI) m/z 345 MH⁺

Example II-43 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-phenyl-ethyl]-amide

MS (ESI) m/z 390 MH⁺

Example II-44 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-phenyl-ethyl]-amide

MS (ESI) m/z 394 MH⁺

Example II-45 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid(2-thiazol-2-yl-ethyl)-amide

MS (ESI) m/z 381 MH⁺

Example II-46 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid(2-thiazol-2-yl-ethyl)-amide

MS (ESI) m/z 385 MH⁺

Example II-47 3-(3-Fluoro-phenyl)-6-methyl-1H-indazole-5-carboxylic acid[(3R)-2-oxo-tetrahydrofuran-3-yl]-amide

MS (ESI) m/z 354 MH⁺

Example II-48 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazole-5-carboxylic acid[(3R)-2-oxo-tetrahydrofuran-3-yl]-amide

MS (ESI) m/z 358 MH⁺

Example II-49 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 326 MH⁺

Example II-50 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid(2-methylsulfanylethyl)amide

MS (ESI) m/z 360 MH⁺

Example II-51 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]amide

MS (ESI) m/z 372 MH⁺

Example II-52 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid[tetrahydrofuran-(2S)-2-ylmethyl]amide

MS (ESI) m/z 370 MH⁺

Example II-53 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid[tetrahydrofuran-(2R)-2-ylmethyl]amide

MS (ESI) m/z 370 MH⁺

Example II-54 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)amide

MS (ESI) m/z 366 MH⁺

Example II-55 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid(5-methylfuran-2-ylmethyl)amide

MS (ESI) m/z 380 MH⁺

Example II-56 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid(thiophen-2-ylmethyl)amide

MS (ESI) m/z 382 MH⁺

Example II-57 3-(3-Fluorophenyl)-7-methoxy-1H-indazole-5-carboxylic acid(benzo[b]furan-2-ylmethyl)amide

MS (ESI) m/z 416 MH⁺

Example II-58 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 310 MH⁺

Example II-59 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid(2-methylsulfanylethyl)amide

MS (ESI) m/z 344 MH⁺

Example II-60 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]amide

MS (ESI) m/z 356 MH⁺

Example II-61 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid[tetrahydrofuran-(2S)-2-ylmethyl]amide

MS (ESI) m/z 354 MH⁺

Example II-62 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid[tetrahydrofuran-(2R)-2-ylmethyl]amide

MS (ESI) m/z 354 MH⁺

Example II-63 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)amide

MS (ESI) m/z 350 MH⁺

Example II-64 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid(5-methylfuran-2-ylmethyl)amide

MS (ESI) m/z 364 MH⁺

Example II-65 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid(thiophen-2-ylmethyl)amide

MS (ESI) m/z 366 MH⁺

Example II-66 3-(3-Fluorophenyl)-7-methyl-1H-indazole-5-carboxylic acid(benzo[b]furan-2-ylmethyl)amide

MS (ESI) m/z 400 MH⁺

Example II-67 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(2-thiophen-2-yl-ethyl)-amide

MS (ESI) m/z 428 MH⁺

Example II-68 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(2-methylsulfanyl-ethyl)-amide

MS (ESI) m/z 392 MH⁺

Example II-69 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-carbamoyl-ethyl]-amide

MS (ESI) m/z 389 MH⁺

Example II-70 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-phenyl-ethyl]-amide

MS (ESI) m/z 438 MH⁺

Example II-71 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(2-thiazol-2-yl-ethyl)-amide

MS (ESI) m/z 429 MH⁺

Example II-72 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(3R)-2-oxo-tetrahydrofuran-3-yl]-amide

MS (ESI) m/z 402 MH⁺

Example II-73 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(tetrahydrofuran-2-ylmethyl)-amide

MS (ESI) m/z 402 MH⁺

Example II-74 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(2-ethoxy-ethyl)-amide

MS (ESI) m/z 390 MH⁺

Example II-75 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidcyclopropylmethyl-amide

MS (ESI) m/z 372 MH⁺

Example II-76 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 398 MH⁺

Example II-77 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(5-methyl-furan-2-ylmethyl)-amide

MS (ESI) m/z 412 MH⁺

Example II-78 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidcyclopropyl-amide

MS (ESI) m/z 358 MH⁺

Example II-79 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid3-methoxy-benzylamide

MS (ESI) m/z 438 MH⁺

Example II-80 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

MS (ESI) m/z 443 MH⁺

Example II-81 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 404 MH⁺

Example II-82 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(furan-3-ylmethyl)-amide

MS (ESI) m/z 398 MH⁺

Example II-83 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(pyridin-2-ylmethyl)-amide

MS (ESI) m/z 409 MH⁺

Example II-84 4-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(thiophen-2-ylmethyl)-amide

MS (ESI) m/z 414 MH⁺

Example II-85 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (2-thiophen-2-yl-ethyl)-amide

MS (ESI) m/z 418 MH⁺

Example II-86 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide

MS (ESI) m/z 382 MH⁺

Example II-87 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid [(1S)-1-carbamoyl-ethyl]-amide

MS (ESI) m/z 379 MH⁺

Example II-88 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid [(1S)-2-hydroxy-1-phenyl-ethyl]-amide

MS (ESI) m/z 428 MH⁺

Example II-89 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (2-thiazol-2-yl-ethyl)-amide

MS (ESI) m/z 419 MH⁺

Example II-90 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid [(3R)-2-oxo-tetrahydrofuran-3-yl]-amide

MS (ESI) m/z 392 MH⁺

Example II-91 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (tetrahydrofuran-2-ylmethyl)-amide

MS (ESI) m/z 392 M⁺

Example II-92 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

MS (ESI) m/z 380 MH⁺

Example II-93 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid cyclopropylmethyl-amide

MS (ESI) m/z 362 MH⁺

Example II-94 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (furan-2-ylmethyl)-amide

MS (ESI) m/z 388 MH⁺

Example II-95 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (5-methyl-furan-2-ylmethyl)-amide

MS (ESI) m/z 402 MH⁺

Example II-96 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid cyclopropylamide

MS (ESI) m/z 348 MH⁺

Example II-97 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid 3-methoxy-benzylamide

MS (ESI) m/z 428 MH⁺

Example II-98 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

MS (ESI) m/z 433 MH⁺

Example II-99 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 394 MH⁺

Example II-100 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (furan-3-ylmethyl)-amide

MS (ESI) m/z 388 MH⁺

Example II-101 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (pyridin-2-ylmethyl)-amide

MS (ESI) m/z 399 MH⁺

Example II-102 3-Benzo[b]furan-2-yl-4-methoxy-1H-indazole-5-carboxylicacid (thiophen-2-ylmethyl)-amide

MS (ESI) m/z 404 MH⁺

Example II-1033-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(2-thiophen-2-yl-ethyl)-amide

MS (ESI) m/z 434 MH⁺

Example II-1043-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(2-methylsulfanyl-ethyl)-amide

MS (ESI) m/z 398 MH⁺

Example II-1053-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid[(1S)-1-carbamoyl-ethyl]-amide

MS (ESI) m/z 395 MH⁺

Example II-1063-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-phenyl-ethyl]-amide

MS (ESI) m/z 444 MH⁺

Example II-1073-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(2-thiazol-2-yl-ethyl)-amide

MS (ESI) m/z 435 MH⁺

Example II-1083-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid[(3R)-2-oxo-tetrahydrofuran-3-yl]-amide

MS (ESI) m/z 408 MH⁺

Example II-1093-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(tetrahydrofuran-2-ylmethyl)-amide

MS (ESI) m/z 408 M⁺

Example II-1103-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(2-ethoxy-ethyl)-amide

MS (ESI) m/z 396 MH⁺

Example II-1113-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acidcyclopropylmethyl-amide

MS (ESI) m/z 378 MH⁺

Example II-1123-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 404 MH⁺

Example II-1133-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(5-methyl-furan-2-ylmethyl)-amide

MS (ESI) m/z 418 MH⁺

Example II-1143-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 364 MH⁺

Example II-1153-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid3-methoxy-benzylamide

MS (ESI) m/z 444 MH⁺

Example II-1163-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

MS (ESI) m/z 449 MH⁺

Example II-1173-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 410 MH⁺

Example II-1183-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(furan-3-ylmethyl)-amide

MS (ESI) m/z 404 MH⁺

Example II-1193-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(pyridin-2-ylmethyl)-amide

MS (ESI) m/z 415 MH⁺

Example II-1203-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazole-5-carboxylic acid(thiophen-2-ylmethyl)-amide

MS (ESI) m/z 420 MH⁺

Example II-121 3-Benzo[b]thiophen-2-yl-4-fluoro-1H-indazole-5-carboxylicacid cyclopropanamide

MS (ESI) m/z 352 MH⁺

Example II-122 3-Benzo[b]thiophen-2-yl-4-fluoro-1H-indazole-5-carboxylicacid (furan-2-ylmethyl)-amide

MS (ESI) m/z 392 MH⁺

Example II-123 3-Benzo[b]thiophen-2-yl-4-fluoro-1H-indazole-5-carboxylicacid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 398 MH⁺

Example II-124 3-Benzo[b]thiophen-2-yl-4-fluoro-1H-indazole-5-carboxylicacid (2-acetylamino-ethyl)-amide

MS (ESI) m/z 397 MH⁺

Example II-125 3-Benzo[b]thiophen-2-yl-4-fluoro-1H-indazole-5-carboxylicacid (2-thiophen-2-yl-ethyl)-amide

MS (ESI) m/z 422 MH⁺

Example II-126 3-Benzo[b]thiophen-2-yl-4-fluoro-1H-indazole-5-carboxylicacid [(1S)-1-carbamoyl-ethyl]]-amide

MS (ESI) m/z 765 2 MH⁺

Example II-127 4-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidcyclopropanamide

MS (ESI) m/z 346 MH⁺

Example II-128 4-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 386 MH⁺

Example II-129 4-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 392 MH⁺

Example II-130 4-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(2-acetylamino-ethyl)-amide

MS (ESI) m/z 391 MH⁺

Example II-131 4-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(2-thiophen-2-yl-ethyl)-amide

MS (ESI) m/z 416 MH⁺

Example II-132 4-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-carbamoyl-ethyl]-amide

MS (ESI) m/z 753 2 MH⁺

Example II-133 3-Benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-carboxylicacid cyclopropanamide

MS (ESI) m/z 336 MH⁺

Example II-134 3-Benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-carboxylicacid (furan-2-ylmethyl)-amide

MS (ESI) m/z 376 MH⁺

Example II-135 3-Benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-carboxylicacid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 382 MH⁺

Example II-136 3-Benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-carboxylicacid (2-acetylamino-ethyl)-amide

MS (ESI) m/z 381 MH⁺

Example II-137 3-Benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-carboxylicacid (2-thiophen-2-yl-ethyl)-amide

MS (ESI) m/z 406 MH⁺

Example II-138 3-Benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-carboxylicacid [(1S)-1-carbamoyl-ethyl]-amide

MS (ESI) m/z 733 2 MH⁺

Example II-139 3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carboxylicacid cyclopropylamide

MS (ESI) m/z 352 MH⁺

Example II-140 3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carboxylicacid (furan-2-ylmethyl)-amide

MS (ESI) m/z 392 MH⁺

Example II-141 3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carboxylicacid [(2S)-tetrahydrofuran-2-ylmethyl]-amide

MS (ESI) m/z 396 MH⁺

Example II-142 3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carboxylicacid [(2R)-tetrahydrofuran-2-ylmethyl]-amide

MS (ESI) m/z 396 MH⁺

Example II-143 3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carboxylicacid (pyridin-3-ylmethyl)-amide

MS (ESI) m/z 403 MH⁺

Example II-144 3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carboxylicacid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 398 MH⁺

Example II-145 3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazole-5-carboxylicacid [3-(2-oxopyrrolidin-1-yl)propyl]-amide

MS (ESI) m/z 437 MH⁺

Example II-146 6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 346 MH⁺

Example II-147 6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 386 MH⁺

Example II-148 6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(2S)-tetrahydrofuran-2-ylmethyl]-amide

MS (ESI) m/z 390 MH⁺

Example II-149 6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(2R)-tetrahydrofuran-2-ylmethyl]-amide

MS (ESI) m/z 390 MH⁺

Example II-150 6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(pyridin-3-ylmethyl)-amide

MS (ESI) m/z 397 MH⁺

Example II-151 6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 392 MH⁺

Example II-152 6-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[3-(2-oxopyrrolidin-1-yl)propyl]amide

MS (ESI) m/z 431 MH⁺

The compounds according to Examples II-153 to II-197 were synthesized bySynthesis Process II-B using the amines produced in Production ExamplesII-18 through II-25.

Example II-153 Cyclopropanecarboxylic acid{3-(3-fluoro-phenyl)-4-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 326 MH⁺

Example II-154 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid{3-(3-fluoro-phenyl)-4-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 369 MH⁺

Example II-155 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid{3-(3-fluoro-phenyl)-4-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 369 MH⁺

Example II-156 Pyridin-3-yl-acetic acid{3-(3-fluoro-phenyl)-4-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 377 MH⁺

Example II-157 Cyclopropanecarboxylic acid{4-bromo-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 376, 378 MH⁺

Example II-158 Pyridin-3-yl-acetic acid{4-bromo-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 425, 427 MH⁺

Example II-159 Cyclopropanecarboxylic acid{4-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 314 MH⁺

Example II-160 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid{4-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 357 MH⁺

Example II-161 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid{4-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 357 MH⁺

Example II-1623-Dimethylamino-N-{4-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-propionamide

MS (ESI) m/z 344 MH⁺

Example II-163

Cyclopropanecarboxylic acid{6-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 314 MH⁺

Example II-164 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid{6-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 357 MH⁺

Example II-165 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid{6-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 357 MH⁺

Example II-166 Pyridin-3-yl-acetic acid{6-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-amide

MS (ESI) m/z 365 MH⁺

Example II-1673-Dimethylamino-N-{6-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl}-propionamide

MS (ESI) m/z 345 MH⁺

Example II-168 Cyclopropanecarboxylic acid{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 326 MH⁺

Example II-169 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 369 MH⁺

Example II-170 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 369 MH⁺

Example II-171 Pyridin-3-yl-acetic acid{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 377 MH⁺

Example II-1723-Dimethylamino-N-{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-propionamide

MS (ESI) m/z 357 MH⁺

Example II-173N-{3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-2-thiophen-2-yl-acetamide

MS (ESI) m/z 382 MH⁺

Example II-174 Furan-2-carboxylic acid{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-amide

MS (ESI) m/z 352 MH⁺

Example II-175N-{3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-3-methoxy-propionamide

MS (ESI) m/z 344 MH⁺

Example II-176 N-[3-(3-Fluorophenyl)-7-methyl-1H-indazol-5-yl]acetamide

MS (ESI) m/z 284 MH⁺

Example II-177

Cyclopropanecarboxylic acid[3-(3-fluorophenyl)-7-methyl-1H-indazol-5-yl]amide

MS (ESI) m/z 310 MH⁺

Example II-178 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid[3-(3-fluorophenyl)-7-methyl-1H-indazol-5-yl]amide

MS (ESI) m/z 353 MH⁺

Example II-179 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid[3-(3-fluorophenyl)-7-methyl-1H-indazol-5-yl]amide

MS (ESI) m/z 353 MH⁺

Example II-180 Tetrahydrofuran-3-carboxylic acid[3-(3-fluorophenyl)-7-methyl-1H-indazol-5-yl]amide

MS (ESI) m/z 340 MH⁺

Example II-181

Tetrahydrofuran-2-carboxylic acid[3-(3-fluorophenyl)-7-methyl-1H-indazol-5-yl]amide

MS (ESI) m/z 340 MH⁺

Example II-182N-[3-(3-Fluorophenyl)-7-methyl-1H-indazol-5-yl]-2-thiophen-2-yl-acetamide

MS (ESI) m/z 366 MH⁺

Example II-183N-[3-(3-Fluorophenyl)-7-methyl-1H-indazol-5-yl]-2-thiophen-3-yl-acetamide

MS (ESI) m/z 366 MH⁺

Example II-184 Cyclopropanecarboxylic acid{6-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl}-amide

MS (ESI) m/z 346 MH⁺

Example II-185 N-(6-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-acetamide

MS (ESI) m/z 320 MH⁺

Example II-186 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid{6-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl}-amide

MS (ESI) m/z 389 MH⁺

Example II-187 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid{6-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl}-amide

MS (ESI) m/z 389 MH⁺

Example II-188 Pyridin-3-yl-acetic acid(6-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 397 MH⁺

Example II-189N-(6-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-2-thiophen-2-yl-acetamide

MS (ESI) m/z 402 MH⁺

Example II-190 Furan-2-carboxylic acid(6-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 372 MH⁺

Example II-191N-(6-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-3-methoxy-propionamide

MS (ESI) m/z 364 MH⁺

Example II-192 Cyclopropanecarboxylic acid(3-benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-amide

MS (ESI) m/z 352 MH⁺

Example II-193N-(3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-acetamide

MS (ESI) m/z 326 MH⁺

Example II-194 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid(3-benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-amide

MS (ESI) m/z 395 MH⁺

Example II-195N-(3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-2-thiophen-2-yl-acetamide

MS (ESI) m/z 408 MH⁺

Example II-196 Furan-2-carboxylic acid(3-benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-amide

MS (ESI) m/z 378 MH⁺

Example II-197N-(3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-3-methoxy-propionamide

MS (ESI) m/z 370 MH⁺

The compounds according to Examples II-198 to II-211 were synthesized bySynthesis Process II-C using the amines produced in Production ExamplesII-26 through II-30.

Example II-198N-{3-(3-Fluoro-phenyl)-4-methoxy-1H-indazol-5-ylmethyl}-3-methoxy-benzamide

MS (ESI) m/z 406 MH⁺

Example II-199N-{6-Fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-ylmethyl}-3-methoxy-benzamide

¹H-NMR (400 MHz, CD₃OD) δ 3.83 (3H, s), 4.73 (2H, d, J=6.0 Hz),7.06-7.18 (2H, m), 7.29 (1H, d, J=10.6 Hz), 7.33-7.76 (6H, m), 8.05 (1H,d, J=7.2 Hz), 8.99 (1H, brs)

Example II-200N-{3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-ylmethyl}-3-methoxy-nicotinamide

MS (ESI) m/z 407 MH⁺

Example II-201N-{3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-ylmethyl}-nicotinamide

MS (ESI) m/z 377 MH⁺

Example II-2023-Cyano-N-{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-ylmethyl}-benzamide

MS (ESI) m/z 401 MH⁺

Example II-2033-Fluoro-N-{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-ylmethyl}-benzamide

MS (ESI) m/z 394 MH⁺

Example II-204N-{6-Fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-ylmethyl}-3-methoxy-nicotinamide

MS (ESI) m/z 395 MH⁺

Example II-205N-{6-Fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-ylmethyl}-nicotinamide

MS (ESI) m/z 365 MH⁺

Example II-2063-Cyano-N-{6-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-ylmethyl}-benzamide

MS (ESI) m/z 389 MH⁺

Example II-2073-Fluoro-N-{6-fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-ylmethyl}-benzamide

MS (ESI) m/z 382 MH⁺

Example II-208N-{6-Fluoro-3-naphthalen-2-yl-1H-indazol-5-ylmethyl}-3-methoxy-benzamide

MS (ESI) m/z 426 MH⁺

Example II-209N-{6-Fluoro-3-naphthalen-2-yl-1H-indazol-5-ylmethyl}-2-methoxy-benzamide

MS (ESI) m/z 426 MH⁺

Example II-210N-(3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-ylmethyl)-3-methoxy-benzamide

MS (ESI) m/z 432 MH⁺

Example II-211N-(3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-ylmethyl)-2-methoxy-benzamide

MS (ESI) m/z 432 MH⁺

The compounds according to Examples II-212 to II-218 were synthesized bySynthesis Process II-D using the amines produced in Production ExamplesII-18, II-19, II-22, II-23, II-24, II-26, and II-28, respectively.

Example II-212N-{3-(3-Fluoro-phenyl)-4-methoxy-1H-indazol-5-yl}-methanesulfonamide

MS (ESI) m/z 336 MH⁺

Example II-213N-{4-Fluoro-3-(3-Fluoro-phenyl)-1H-indazol-5-yl}-methanesulfonamide

MS (ESI) m/z 324 MH⁺

Example II-214N-{3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-methanesulfonamide

MS (ESI) m/z 336 MH⁺

Example II-215N-[3-(3-Fluorophenyl)-7-methyl-1H-indazol-5-yl]methanesulfonamide

MS (ESI) m/z 320 MH⁺

Example II-216N-{3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-ylmethyl}-3-methoxy-benzenesulfonamide

MS (ESI) m/z 442 MH⁺

Example II-217N-{6-Fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-ylmethyl}-3-methoxy-benzenesulfonamide

MS (ESI) m/z 430 MH⁺

Example II-218N-(3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-yl)-methanesulfonamide

MS (ESI) m/z 362 MH⁺

The compounds according to Examples II-219 to II-225 were synthesized bySynthesis Process II-E using the amines produced in Production ExamplesII-18 through II-25, respectively.

Example II-219 3-(3-Fluoro-phenyl)-4-methoxy-1H-indazol-5-yl-amine

MS (ESI) m/z 258 MH⁺

Example II-220 4-Bromo-3-(3-fluoro-phenyl)-1H-indazol-5-yl-amine

MS (ESI) m/z 306, 308 MH⁺

Example II-221 4-Fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl-amine

MS (ESI) m/z 246 MH⁺

Example II-222 6-Fluoro-3-(3-fluoro-phenyl)-1H-indazol-5-yl-amine

MS (ESI) m/z 246 MH⁺

Example II-223 3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-yl-amine

MS (ESI) m/z 258 MH⁺

Example II-224 6-Fluoro-3-naphthalen-2-yl-1H-indazol-5-ylamine

MS (ESI) m/z 278 MH⁺

Example II-225 3-Benzo[b]thiophen-2-yl-6-fluoro-1H-indazol-5-ylamine

MS (ESI) m/z 284 MH⁺

Example II-226-a Cyclopropanecarboxylic acid{4-bromo-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl}-amide

A total of 513 mg of4-bromo-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl-amine obtained inProduction Example II-21 was dissolved in 19 ml of tetrahydrofuran.Under ice-cooling and stirring, 0.261 ml of triethylamine and 0.089 mlof cyclopropanecarbonyl chloride were added, and the mixture was stirredat room temperature for 90 minutes. Water was added to the reactionmixture, followed by extracting with ethyl acetate. The resultingorganic layer was washed with brine, dried over magnesium sulfate andthe solvent was evaporated. The residue was purified and separated bysilica gel column chromatography (ethyl acetate:hexane=1:2), to give 471mg of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.90 (2H, m), 1.02-1.09 (2H, m),1.53-1.60 (1H, m), 6.45 (1H, d, J=9.2 Hz), 7.05-7.13 (1H, m), 7.19-7.93(20H, m)

Example II-226-b5-(Cyclopropanecarbonyl-amide)-3-(3-fluoro-phenyl)-1-trityl-1H-indazole-4-carboxylicacid

A total of 17.8 mg of the title compound was obtained by the procedureof Production Example II-2-d, except from 144 mg ofcyclopropanecarboxylic acid{4-bromo-3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-yl}amide obtained inExample II-226-a.

¹H-NMR (400 MHz, CD₃OD) δ 0.72-1.71 (5H, m), 6.48 (1H, d, J=9.2 Hz),6.98-7.05 (1H, m), 7.20-7.50 (19H, m)

Example II-226-c5-(Cyclopropanecarbonyl-amide)-3-(3-fluoro-phenyl)-1H-indazole-4-carboxylicacid

178 mg of5-(cyclopropanecarbonyl-amide)-3-(3-fluoro-phenyl)-1-trityl-1H-indazole-4-carboxylicacid obtained in Example II-226-b was dissolved in 2 ml oftetrahydrofuran and 2 ml of dichloromethane. 0.5 ml of trifluoroaceticacid was added, followed by stirring at room temperature for 16 hours.Water was added to the reaction mixture, followed by extracting withethyl acetate. The resulting organic layer was washed with brine, driedover magnesium sulfate and the solvent was evaporated. The residue waspurified and separated by silica gel column chromatography (ethylacetate), to give 96.9 mg of the title compound as pale pink crystals.

¹H-NMR (400 MHz, CD₃OD) δ 0.83-1.00 (4H, m), 1.73-1.83 (1H, m),7.10-7.17 (1H, m), 7.23-7.28 (1H, m), 7.31-7.36 (1H, m), 7.44 (1H, dt,J=6.0, 8.0 Hz), 7.68 (1H, d, J=9.2 Hz), 7.87 (1H, d, J=9.2 Hz)

Example II-227N-{3-(3-Fluoro-phenyl)-6-methoxy-1H-indazol-5-ylmethyl}-3-methoxy-benzamide

A total of 25.6 mg ofC-{3-(3-fluoro-phenyl)-6-methoxy-1H-indazol-5-yl}-methylamine obtainedin Production Example 26 was dissolved in 1.9 ml of dimethylformamide,15.3 mg of 1-hydroxybenzotriazole, 0.066 ml of diisopropylethylamine and14.4 mg of 3-methoxybenzoic acid were added thereto, and 27.2 mg of1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (i.e.,WSC.HCl) was added thereto under ice-cooling and stirring. Afterstirring at room temperature for 5 hours, water was added and themixture was extracted with ethyl acetate. The resulting organic layerwas washed with 0.5 N aqueous sodium hydroxide solution, 1 Nhydrochloric acid and saturated brine, dried over magnesium sulfate, andthe solvent was evaporated. The residue was purified and separated bysilica gel column chromatography (dichloromethane:methanol=10:1), togive 9.24 mg of the title compound as pale yellow crystals.

¹H-NMR (400 MHz, CD₃OD) δ 3.83 (3H, s), 3.98 (3H, s), 4.66 (2H, s), 7.03(1H, s), 7.07-7.14 (2H, m), 7.34-7.43 (3H, m), 7.47 (1H, dt, J=6.0, 8.0Hz), 7.59-7.64 (1H, m), 7.72 (1H, d, J=8.0 Hz), 7.89 (1H, s).

The compounds according to Examples II-228 to II-265 were synthesized bySynthesis Process II-A using the carboxylic acids produced in ProductionExamples II-31 and II-32, respectively.

Example II-228 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 314 MH⁺

Example II-229 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acidcyclopropylmethylamide

MS (ESI) m/z 328 MH⁺

Example II-230 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid(2-methylsulfanylethyl)amide

MS (ESI) m/z 348 MH⁺

Example II-231 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methylpropyl]amide

MS (ESI) m/z 360 MH⁺

Example II-232 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-phenylethyl]amide

MS (ESI) m/z 394 MH⁺

Example II-233 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(2R)-tetrahydrofuran-2-ylmethyl]amide

MS (ESI) m/z 358 MH⁺

Example II-234 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(2S)-tetrahydrofuran-2-ylmethyl]amide

MS (ESI) m/z 358 MH⁺

Example II-235 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-3-methylsulfanylpropyl]amide

MS (ESI) m/z 392 MH⁺

Example II-236 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid(2-hydroxy-1-hydroxymethylethyl)amide

MS (ESI) m/z 348 MH⁺

Example II-237 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-3-methylbutyl]amide

MS (ESI) m/z 374 MH⁺

Example II-238 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-(1H-imidazol-4-ylmethyl)ethyl]amide

MS (ESI) m/z 398 MH⁺

Example II-239 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(1S)-1-carbamoylethyl]amide

MS (ESI) m/z 345 MH⁺

Example II-240 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid[(3R)-2-oxo-tetrahydrofuran-3-yl]amide

MS (ESI) m/z 358 MH⁺

Example II-241 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)amide

MS (ESI) m/z 354 MH⁺

Example II-242 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid(5-methylfuran-2-ylmethyl)amide

MS (ESI) m/z 368 MH⁺

Example II-243 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid(furan-3-ylmethyl)amide

MS (ESI) m/z 354 MH⁺

Example II-244 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid(benzo[b]furan-2-ylmethyl)amide

MS (ESI) m/z 404 MH⁺

Example II-245 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acidthiophen-2-ylmethyl)amide

MS (ESI) m/z 370 Mm

Example II-246 7-Fluoro-3-(3-fluorophenyl)-1H-indazole-5-carboxylic acid(pyridin-3-ylmethyl)amide

MS (ESI) m/z 365 MH⁺

Example II-247 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 346 MH⁺

Example II-248 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidcyclopropylmethylamide

MS (ESI) m/z 360 MH⁺

Example II-249 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(2-methylsulfanylethyl)amide

MS (ESI) m/z 380 MH⁺

Example II-250 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methylpropyl]amide

MS (ESI) m/z 392 MH⁺

Example II-251 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-phenylethyl]amide

MS (ESI) m/z 426 MH⁺

Example II-252 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(2R)-tetrahydrofuran-2-ylmethyl]amide

MS (ESI) m/z 390 MH⁺

Example II-253 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(2S)-tetrahydrofuran-2-ylmethyl]amide

MS (ESI) m/z 390 MH⁺

Example II-254 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-3-methylsulfanylpropyl]amide

MS (ESI) m/z 424 MH⁺

Example II-255 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(2-hydroxy-1-hydroxymethylethyl)amide

MS (ESI) m/z 380 MH⁺

Example II-256 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-3-methylbutyl]amide

MS (ESI) m/z 406 MH⁺

Example II-257 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-(1H-imidazol-4-ylmethyl)ethyl]amide

MS (ESI) m/z 430 MH⁺

Example II-258 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-carbamoylethyl]amide

MS (ESI) m/z 377 MH⁺

Example II-259 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(3R)-2-oxo-tetrahydrofuran-3-yl]amide

MS (ESI) m/z 390 MH⁺

Example II-260 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)amide

MS (ESI) m/z 386 MH⁺

Example II-261 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(5-methylfuran-2-ylmethyl)amide

MS (ESI) m/z 400 MH⁺

Example II-262 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(furan-3-ylmethyl)amide

MS (ESI) m/z 386 MH⁺

Example II-263 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(benzo[b]furan-2-ylmethyl)amide

MS (ESI) m/z 436 MH⁺

Example II-264 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(thiophen-2-ylmethyl)-amide

MS (ESI) m/z 402 MH⁺

Example II-265 7-Fluoro-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(pyridin-3-ylmethyl)amide

MS (ESI) m/z 397 MH⁺

The compounds according to Examples II-266 and II-267 were synthesizedby Synthesis Process II-D using the amines produced in ProductionExamples II-33 and II-34, respectively.

Example II-266N-(3-Benzo[b]thiophen-2-yl-4-fluoro-1H-indazol-5-yl)-methanesulfonamide

MS (ESI) m/z 362 MH⁺

Example II-267N-(4-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-methanesulfonamide

MS (ESI) m/z 356 MH⁺

The compounds according to Examples II-268 to II-278 were synthesized bySynthesis Process II-B using the amines produced in Production ExamplesII-33 and II-34, respectively.

Example II-268

Cyclopropanecarboxylic acid(3-benzo[b]thiophen-2-yl-4-fluoro-1H-indazol-5-yl)-amide

MS (ESI) m/z 352 MH⁺

Example II-269 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid(3-benzo[b]thiophen-2-yl-4-fluoro-1H-indazol-5-yl)-amide

MS (ESI) m/z 395 MH⁺

Example II-270 Tetrahydrofuran-2-carboxylic acid(3-benzo[b]thiophen-2-yl-4-fluoro-1H-indazol-5-yl)-amide

MS (ESI) m/z 382 MH⁺

Example II-271 Furan-2-carboxylic acid(3-benzo[b]thiophen-2-yl-4-fluoro-1H-indazol-5-yl)-amide

MS (ESI) m/z 378 MH⁺

Example II-272N-(3-Benzo[b]thiophen-2-yl-4-fluoro-1H-indazol-5-yl)-2-thiophen-2-yl-acetamide

MS (ESI) m/z 408 MH⁺

Example II-273 Thiophene-2-carboxylic acid(3-benzo[b]thiophen-2-yl-4-fluoro-1H-indazol-5-yl)-amide

MS (ESI) m/z 394 MH⁺

Example II-274 Cyclopropanecarboxylic acid(4-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 346 MH⁺

Example II-275 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid(4-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 389 MH⁺

Example II-276 Tetrahydrofuran-2-carboxylic acid(4-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 376 MH⁺

Example II-277 Furan-2-carboxylic acid(4-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 372 MH⁺

Example II-278N-(4-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-2-thiophen-2-yl-acetamide

MS (ESI) m/z 402 MH⁺

The compounds according to Examples II-279 to II-282 were synthesized bySynthesis Process II-A using the carboxylic acid produced in ProductionExample II-35.

Example II-279 3-Benzo[b]furan-2-yl-4-propoxy-1H-indazole-5-carboxylicacid cyclopropylamide

MS (ESI) m/z 376 MH⁺

Example II-280 3-Benzo[b]furan-2-yl-4-propoxy-1H-indazole-5-carboxylicacid (furan-2-ylmethyl)amide

MS (ESI) m/z 416 MH⁺

Example II-281 3-Benzo[b]furan-2-yl-4-propoxy-1H-indazole-5-carboxylicacid ((1S)-1-hydroxymethyl-2-methyl-propyl)-amide

MS (ESI) m/z 422 MH⁺

Example II-282 3-Benzo[b]furan-2-yl-4-propoxy-1H-indazole-5-carboxylicacid ((1S)-2-hydroxy-1-phenyl-ethyl)-amide

MS (ESI) m/z 456 MH⁺

The compounds according to Examples II-283 to II-315 were synthesized bySynthesis Process II-B using the amines produced in Production ExamplesII-36 through II-39, respectively.

Example II-283 N-[7-Fluoro-3-(3-fluorophenyl)-1H-indazol-5-yl]acetamide

MS (ESI) m/z 288 MH⁺

Example II-284 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid[7-fluoro-3-(3-fluorophenyl)-1H-indazol-5-yl]amide

MS (ESI) m/z 357 MH⁺

Example II-285 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid[7-fluoro-3-(3-fluorophenyl)-1H-indazol-5-yl]amide

MS (ESI) m/z 357 MH⁺

Example II-286 Tetrahydrofuran-3-carboxylic acid[7-fluoro-3-(3-fluorophenyl)-1H-indazol-5-yl]amide

MS (ESI) m/z 344 MH⁺

Example II-287 Tetrahydrofuran-2-carboxylic acid[7-fluoro-3-(3-fluorophenyl)-1H-indazol-5-yl]amide

MS (ESI) m/z 344 MH⁺

Example II-288N-[7-Fluoro-3-(3-fluorophenyl)-1H-indazol-5-yl]-2-thiophen-3-ylacetamide

MS (ESI) m/z 370 MH⁺

Example II-289N-[7-Fluoro-3-(3-fluorophenyl)-1H-indazol-5-yl]-2-thiophen-2-ylacetamide

MS (ESI) m/z 370 MH⁺

Example II-290 N-(7-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)acetamide

MS (ESI) m/z 320 MH⁺

Example II-291 Cyclopropylcarboxylic acid(7-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)amide

MS (ESI) m/z 346 MH⁺

Example II-292 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid(7-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)amide

MS (ESI) m/z 389 MH⁺

Example II-293 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid(7-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)amide

MS (ESI) m/z 389 MH⁺

Example II-294 Tetrahydrofuran-3-carboxylic acid(7-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)amide

MS (ESI) m/z 376 MH⁺

Example II-295 Tetrahydrofuran-2-carboxylic acid(7-fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)amide

MS (ESI) m/z 376 MH⁺

Example II-296N-(7-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-2-thiophen-3-ylacetamide

MS (ESI) m/z 402 MH⁺

Example II-297N-(7-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)-2-thiophen-2-ylacetamide

MS (ESI) m/z 402 MH⁺

Example II-298 N-(4-Methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)-acetamide

MS (ESI) m/z 332 MH⁺

Example II-299 Cyclopropanecarboxylic acid(4-methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 358 MH⁺

Example II-300 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid(4-methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 401 MH⁺

Example II-301 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid(4-methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 401 MH⁺

Example II-302 Furan-2-carboxylic acid(4-methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 384 MH⁺

Example II-303 Thiophene-2-carboxylic acid(4-methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)-amide

MS (ESI) m/z 400 M⁺

Example II-304N-(4-Methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)-2-thiophen-2-yl-acetamide

MS (ESI) m/z 414 MH⁺

Example II-3053-Methoxy-N-(4-methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)propionamide

MS (ESI) m/z 376 MH⁺

Example II-3063-Dimethylamino-N-(4-methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)propionamide

MS (ESI) m/z 389 MH⁺

Example II-307N-(3-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-acetamide

MS (ESI) m/z 338 MH⁺

Example II-308

Cyclopropanecarboxylic acid(3-benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-amide

MS (ESI) m/z 364 MH⁺

Example II-309 (2R)-5-Oxo-pyrrolidine-2-carboxylic acid(3-benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-amide

MS (ESI) m/z 407 MH⁺

Example II-310 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid(3-benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-amide

MS (ESI) m/z 407 MH⁺

Example II-311 Furan-2-carboxylic acid(3-benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-amide

MS (ESI) m/z 390 MH⁺

Example II-312 Thiophene-2-carboxylic acid(3-benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-amide

MS (ESI) m/z 406 M⁺

Example II-313N-(3-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-2-thiophen-2-yl-acetamide

MS (ESI) m/z 420 MH⁺

Example II-314N-(3-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-3-methoxy-propionamide

MS (ESI) m/z 382 MH⁺

Example II-315N-(3-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-3-dimethylamino-propionamide

MS (ESI) m/z 395 MH⁺

The compounds according to Examples II-316 to II-319 were synthesized bySynthesis Process II-C using the amine produced in Production ExampleII-40.

Example II-316N-(7-Fluoro-3-naphthalen-2-yl-1H-indazol-5-ylmethyl)-3-methoxybenzamide

MS (ESI) m/z 426 MH⁺

Example II-317N-(7-Fluoro-3-naphthalen-2-yl-1H-indazol-5-ylmethyl)-2-methoxybenzamide

MS (ESI) m/z 426 MH⁺

Example II-3183-Cyano-N-(7-fluoro-3-naphthalen-2-yl-1H-indazol-5-ylmethyl)benzamide

MS (ESI) m/z 421 MH⁺

Example II-3193-Fluoro-N-(7-fluoro-3-naphthalen-2-yl-1H-indazol-5-ylmethyl)benzamide

MS (ESI) m/z 414 MH⁺

The compounds according to Examples II-320 to II-323 were synthesized bySynthesis Process II-D using the amines produced in Production ExamplesII-36 through II-39, respectively.

Example II-320N-[7-Fluoro-3-(3-fluorophenyl)-1H-indazol-5-yl]methanesulfonamide

MS (ESI) m/z 324 MH⁺

Example II-321N-(7-Fluoro-3-naphthalen-2-yl-1H-indazol-5-yl)methanesulfonamide

MS (ESI) m/z 356 MH⁺

Example II-322N-(4-Methoxy-3-naphthalen-2-yl-1H-indazol-5-yl)-methanesulfonamide

MS (ESI) m/z 368 MH⁺

Example II-323N-(3-Benzo[b]thiophen-2-yl-4-methoxy-1H-indazol-5-yl)-methanesulfonamide

MS (ESI) m/z 374 MH⁺

The compounds according to Examples II-324 to II-340 were synthesized bySynthesis Process II-A using the carboxylic acids produced in ProductionExamples II-41 and II-42, respectively.

Example II-324 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 358 MH⁺

Example II-325 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(3R)-2-oxo-tetrahydro-furan-3-yl]-amide

MS (ESI) m/z 402 MH⁺

Example II-326 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 398 MH⁺

Example II-327 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-phenyl-ethyl]-amide

MS (ESI) m/z 438 MH⁺

Example II-328 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 404 MH⁺

Example II-329 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acidcyclopropylmethylamide

MS (ESI) m/z 372 MH⁺

Example II-330 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(thiophen-2-ylmethyl)-amide

MS (ESI) m/z 414 M⁺

Example II-331 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid[(1S)-1-carbamoyl-ethyl]-amide

MS (ESI) m/z 389 MH⁺

Example II-332 6-Methoxy-3-naphthalen-2-yl-1H-indazole-5-carboxylic acid(tetrahydrofuran-2-ylmethyl)-amide

MS (ESI) m/z 402 MH⁺

Example II-3333-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acidcyclopropylamide

MS (ESI) m/z 364 MH⁺

Example II-3343-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acid[(3R)-2-oxo-tetrahydro-furan-3-yl]-amide

MS (ESI) m/z 408 MH⁺

Example II-3353-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acid(furan-2-ylmethyl)-amide

MS (ESI) m/z 404 MH⁺

Example II-3363-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acid[(1S)-2-hydroxy-1-phenyl-ethyl]-amide

MS (ESI) m/z 444 MH⁺

Example II-3373-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acid[(1S)-1-hydroxymethyl-2-methyl-propyl]-amide

MS (ESI) m/z 410 MH⁺

Example II-3383-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acidcyclopropylmethyl-amide

MS (ESI) m/z 378 MH⁺

Example II-3393-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acid(thiophen-2-ylmethyl)-amide

MS (ESI) m/z 420 MH⁺

Example II-3403-Benzo[b]thiophen-2-yl-6-methoxy-1H-indazole-5-carboxylic acid(tetrahydrofuran-2-ylmethyl)-amide

MS (ESI) m/z 408 MH⁺

The compounds according to Examples II-341 to II-344 were synthesized bySynthesis Process II-B using the amine produced in Production ExampleII-43.

Example II-341

Cyclopropanecarboxylic acid(3-benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-yl)-amide

MS (ESI) m/z 336 MH⁺

Example II-342 (2S)-5-Oxo-pyrrolidine-2-carboxylic acid(3-benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-yl)-amide

MS (ESI) m/z 379 MH⁺

Example II-343 Furan-2-carboxylic acid(3-benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-yl)-amide

MS (ESI) m/z 362 MH⁺

Example II-344N-(3-Benzo[b]furan-2-yl-4-fluoro-1H-indazole-5-yl)-2-thiophen-2-yl-acetamide

MS (ESI) m/z 392 MH⁺

The compounds (I) according to the present invention or a salt thereofexhibited an excellent action in tests for determining JNK inhibitoryaction. For example, the inhibitory actions on JNK 3 were as follows.

Test Example 1 Determination of JNK 3 Inhibition

Human JNK 3 was expressed as a fusion protein (GST-JNK 3) withglutathione S-transferase (GST) in Escherichia coli and was purifiedusing glutathione Sepharose 4B beads. The amino acid sequence 1-169 ofc-Jun was peppered as a fusion protein (GST-c-Jun) with GST inEscherichia coli, was purified using glutathione Sepharose 4B beads andwas used as a substrate. A test compound was diluted with 100% dimethylsulfoxide into 10 mM and was then further diluted with 10% aqueousdimethyl sulfoxide solution to yield a dilution series. To each well of96-well OPTI plate (available from Packard) were placed 20 μl of thediluted compound, 30 μl of a substrate solution (1.2 μg of GST-c-Jun,0.04 μg of GST-JNK 3, 0.2 μCi of [γ-³³P]ATP, 25 mM of HEPES pH=7.5, 10mM of magnesium acetate, and 3.33 μM of ATP), and 50 μl of an enzymesolution (0.04 μg of GST-JNK 3, 25 mM of HEPES pH=7.5, and 10 mMmagnesium acetate) up to 100 μl, and the mixture was allowed to reactfor 30 minutes. After terminating the reaction by adding 100 μl of areaction terminator (80 mM ATP, 50 mg/ml glutathione SPA beads(available from Amersham Pharmacia Biotech)), the reaction mixture wasshaken for 30 minutes. The mixture was centrifuged at room temperatureat 1000×g for 5 minutes, and the emission intensity thereof wasdetermined on a TopCount™ illuminator (available from Packard). Theactivity is expressed by the 50% inhibitory concentration on theenzymatic activity of JNK, i.e., IC₅₀ (nM). Results: The compounds (I)according to the present invention or a salt thereof showed an excellentJNK 3-inhibitory activity. Examples of IC₅₀ thereof will be shown below.

Ex. No. IC₅₀ I-16 51 nM I-26 113 nM I-48 109 nM I-55 52 nM I-94 163 nMII-5 100 nM II-93 137 nM II-126 143 nM II-184 86 nM II-189 194 nM I-10455 nM I-132 197 nM I-137 54 nM I-143 221 nM I-163 80 nM II-208 143 nMII-218 215 nM II-259 148 nM II-281 84 nM II-288 71 nM

The structural formulae of the compounds according to Productionexamples and Examples will be listed below.

1. A compound represented by the following formula or a salt thereof

wherein R¹ is a 2-thienyl, 2-furyl, 2-benzofuryl, or 2-benzothienylgroup, each of which may be substituted; R², R⁴, and R⁵ eachindependently represent a hydrogen atom, a halogen atom, a hydroxylgroup, a cyano group, a nitro group, a carboxyl group, a C₁-C₆ alkylgroup which may be substituted, a C₁-C₆ alkoxy group which may besubstituted, a C₂-C₇ acyl group which may be substituted,—CO—NR^(2a)R^(2b), —NR^(2b)CO—R^(2a), or —NR^(2a)R^(2b), wherein R^(2a)and R^(2b) each independently represent a hydrogen atom or a C₁-C₆ alkylgroup which may be substituted, provided that at least one of R², R⁴,and R⁵ is not a hydrogen atom; L is a single bond, a C₁-C₆ alkylenegroup which may be substituted, a C₂-C₆ alkenylene group which may besubstituted, or a C₂-C₆ alkynylene group which may be substituted; X isa single bond, or a group represented by —NR⁶—, —O—, —CO—, —S—, —SO—,—SO₂—, —CO—NR⁸—V²—, —C(O)O—, —NR⁸—C(O)O—, —NR⁸—S—, —NR⁸—SO—,—NR⁸—SO₂—V²—, —NR⁹—CO—NR¹⁰—, —NR⁹—CS—NR¹⁰—, —S(O)_(m)—NR¹¹—V²—,—C(═NR¹²)—NR¹³—, —OC(O)—, —OC(O)—N—R¹⁴— or —CH₂—NR⁸—COR⁶, wherein R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ each independently represent ahydrogen atom, a halogen atom, a hydroxyl group, a C₁-C₆ alkyl groupwhich may be substituted, a C₂-C₆ alkenyl group which may besubstituted, a C₂-C₆ alkynyl group which may be substituted, a C₁-C₆alkoxy group which may be substituted, a C₂-C₆ alkenyloxy group whichmay be substituted, a C₁-C₆ alkylthio group which may be substituted, aC₂-C₆ alkenylthio group which may be substituted, a C₃-C₈ cycloalkylgroup which may be substituted, a C₃-C₈ cycloalkenyl group which may besubstituted, a 5- to 14-membered non-aromatic heterocyclic group whichmay be substituted, a C₆-C₁₄ aromatic cyclic hydrocarbon group which maybe substituted or a 5- to 14-membered aromatic heterocyclic group whichmay be substituted; V² is a single bond or a C₁-C₆ alkylene group whichmay be substituted; and m is 0, 1 or 2; and Y is a hydrogen atom, ahalogen atom, a nitro group, a hydroxyl group, a cyano group, a carboxylgroup, a C₁-C₆ alkyl group which may be substituted, a C₂-C₆ alkenylgroup which may be substituted, a C₂-C₆ alkynyl group which may besubstituted, a C₁-C₆ alkoxy group which may be substituted, a C₃-C₈cycloalkyl group which may be substituted, a C₃-C₈ cycloalkenyl groupwhich may be substituted, a 5- to 14-membered non-aromatic heterocyclicgroup which may be substituted, a C₆-C₁₄ aromatic cyclic hydrocarbongroup which may be substituted, a 5- to 14-membered aromaticheterocyclic group which may be substituted, an amino group or —W—R¹⁵,wherein W is —CO— or —SO₂—; and R¹⁵ is a C₁-C₆; alkyl group which may besubstituted, a C₆-C₁₄ aromatic cyclic hydrocarbon group which may besubstituted, a 5- to 14-membered aromatic heterocyclic group which maybe substituted or an amino group.
 2. The compound according to claim 1or a salt thereof, wherein R², R⁴ and R⁵ each independently represent ahydrogen atom, a halogen atom, or a C₁-C₆ alkoxy group which may besubstituted.
 3. The compound according to claim 1 or a salt thereof,wherein R⁵ is a hydrogen atom.
 4. The compound according to claim 1 or asalt thereof, wherein R⁴ is a hydrogen atom.
 5. The compound accordingto claim 1 or a salt thereof, wherein R² is a hydrogen atom.
 6. Thecompound according to claim 1 or a salt thereof, wherein L is a singlebond or a methylene group.
 7. The compound according to claim 1 or asalt thereof, wherein L is a single bond.
 8. The compound according toclaim 1 or a salt thereof, wherein X is a group represented by—CO—NR⁸—V²— or —NR⁸—SO₂—V²—.
 9. The compound according to claim 15 or asalt thereof, wherein R⁸ is a hydrogen atom.
 10. The compound accordingto claim 1 or a salt thereof, wherein Y is a C₁-C₆ alkyl group, a C₆-C₁₄aromatic cyclic hydrocarbon group, a C₁-C₆ alkoxy group, a C₃-C₈cycloalkyl group, a 5- to 14-membered non-aromatic heterocyclic groupand a 5- to 14-membered aromatic heterocyclic group, and Y is a groupwhich may be substituted by one to three members selected fromSubstituent Group “a2”: <Substituent Group “a2”> (1) (a) C₁-C₆ alkylgroups, (b) C₂-C₆ alkenyl groups, (c) C₂-C₆ alkynyl groups, (d) C₁-C₆alkoxy groups, (e) C₂-C₇ acyl groups, (f) an amide group, (g) an aminogroup, (h) a C₃-C₈ cycloalkyl group, (i) C₃-C₈ cycloalkenyl groups, (j)C₆-C₁₄ aromatic cyclic hydrocarbon groups, (k) 5- to 14-memberedaromatic heterocyclic groups, (l) C₆-C₁₄ aryloxy groups, and (m) 5- to14-membered non-aromatic heterocyclic groups, each of which may besubstituted by one to three members selected from Substituent Group“b2”, (2) halogen atoms, (3) a hydroxyl group, (4) a nitro group, (5) acyano group, and (6) a carboxyl group: <Substituent Group “b2”> C₁-C₆alkyl groups, halogen atoms, a hydroxyl group, a nitro group, a cyanogroup, and a carboxyl group.
 11. The compound according to claim 10 or asalt thereof, wherein Substituent Group “a2” is (1) (a) C₁-C₆ alkylgroups, (b) C₁-C₆ alkoxy groups, (c) C₁-C₇ acyl groups, (d) an amidegroup, (e) an amino group, and (f) C₃-C₈ cycloalkyl groups, each ofwhich may be substituted by one to three groups selected from thefollowing Substituent Group “b2”, (2) halogen atoms, (3) a hydroxylgroup, (4) a nitro group, (5) a cyano group, and (6) a carboxyl group,and Substituent Group “b2” is C₁-C₆ alkyl groups, halogen atoms, ahydroxyl group, a nitro group, a cyano group, and a carboxyl group. 12.The compound according to claim 10 or a salt thereof, whereinSubstituent Group “a2” is (1) C₁-C₆ alkoxy groups, (2) halogen atoms,and (3) a cyano group.
 13. The compound according to claim 1 or a saltthereof, wherein Y is a C₃-C₈ cycloalkyl group, a phenyl group, a 5- or6-membered non-aromatic heterocyclic group or a 5- or 6-memberedaromatic heterocyclic group, and Y is a group which may be substitutedby one to three members selected from Substituent Group “a2”:<Substituent Group “a2”> (1) (a) C₁-C₆ alkyl groups, (b) C₂-C₆ alkenylgroups, (c) C₂-C₆ alkynyl groups, (d) C₁-C₆ alkoxy groups, (e) C₂-C₇acyl groups, (f) an amide group, (g) an amino group, (h) a C₃-C₈cycloalkyl group, (i) C₃-C₈ cycloalkenyl groups, (j) C₆-C₁₄ aromaticcyclic hydrocarbon groups, (k) 5- to 14-membered aromatic heterocyclicgroups, (l) C₆-C₁₄ aryloxy groups, and (m) 5- to 14-memberednon-aromatic heterocyclic groups, each of which may be substituted byone to three members selected from Substituent Group “b2”, (2) halogenatoms, (3) a hydroxyl group, (4) a nitro group, (5) a cyano group, and(6) a carboxyl group: <Substituent Group “b2”> C₁-C₆ alkyl groups,halogen atoms, a hydroxyl group, a nitro group, a cyano group, and acarboxyl group.
 14. The compound according to claim 1 or a salt thereof,wherein Y is a furyl group, a thienyl group, a pyrrolyl group, a phenylgroup, a pyridyl group, a C₃-C₈ cycloalkyl group, a tetrahydrofuran-ylgroup, a tetrahydrothiophenyl group, a pyrrolidinyl group, atetrahydrofuran-2-one-yl group, a pyrrolidin-2-one-yl group or a grouprepresented by the formula

wherein Y^(2a) is a group represented by —CONH₂ or —CH₂OH; and Y^(2b)and Y^(2c) each independently represent a hydrogen atom, a phenyl groupwhich may be substituted or a C₁-C₆ alkyl group which may besubstituted), and wherein Y is a group which may be substituted by oneto three members selected from the Substituent Group “a2”: <SubstituentGroup “a2”> (1) (a) C₁-C₆ alkyl groups, (b) C₂-C₆ alkenyl groups, (c)C₂-C₆ alkynyl groups, (d) C₁-C₆ alkoxy groups, (e) C₂-C₇ acyl groups,(f) an amide group, (g) an amino group, (h) a C₃-C₈ cycloalkyl group,(i) C₃-C₈ cycloalkenyl groups, (j) C₆-C₁₄ aromatic cyclic hydrocarbongroups, (k) 5- to 14-membered aromatic heterocyclic groups, (l) C₆-C₁₄aryloxy groups, and (m) 5- to 14-membered non-aromatic heterocyclicgroups, each of which may be substituted by one to three membersselected from Substituent Group “b2”, (2) halogen atoms, (3) a hydroxylgroup, (4) a nitro group, (5) a cyano group, and (6) a carboxyl group:<Substituent Group “b2”> C₁-C₆ alkyl groups, halogen atoms, a hydroxylgroup, a nitro group, a cyano group, and a carboxyl group.
 15. Thecompound according to claim 1 or a salt thereof, wherein Y is a furylgroup or a thienyl group; and Y is a group which may be substituted byone to three members selected from the Substituent Group “a2”:<Substituent Group “a2”> (1) (a) C₁-C₆ alkyl groups, (b) C₂-C₆ alkenylgroups, (c) C₂-C₆ alkynyl groups, (d) C₁-C₆ alkoxy groups, (e) C₂-C₇acyl groups, (f) an amide group, (g) an amino group, (h) a C₃-C₈cycloalkyl group, (i) C₃-C₈ cycloalkenyl groups, (j) C₆-C₁₄ aromaticcyclic hydrocarbon groups, (k) 5- to 14-membered aromatic heterocyclicgroups, (l) C₆-C₁₄ aryloxy groups, and (m) 5- to 14-memberednon-aromatic heterocyclic groups, each of which may be substituted byone to three members selected from Substituent Group “b2”, (2) halogenatoms, (3) a hydroxyl group, (4) a nitro group, (5) a cyano group, and(6) a carboxyl group: <Substituent Group “b2”> C₁-C₆ alkyl groups,halogen atoms, a hydroxyl group, a nitro group, a cyano group, and acarboxyl group.
 16. A pharmaceutical composition comprising the compoundaccording to claim 1 or a salt thereof, and a pharmacologicallyacceptable carrier.